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Antibody-Drug Conjugates: Possibilities and Challenges.

Introduction

Similar to conventional cancer treatments such as chemotherapy and radiotherapy, antibody immunotherapy and targeted therapies based on nanoparticulate structures are not safe and efficacious as often claimed; therefore, alternative therapies are urgently needed. In this regard, Antibody Drug Conjugates (ADC) technology that could bring forth a new generation of cancer therapeutics was the main focus of this study. ADCs are monoclonal antibodies (mAbs) connected by a specified linkage to antitumor cytotoxic molecules. The main components of an ADC and mechanism of its action are further demonstrated in figure 1.

In ADC technology, the specificity of an antibody for its immunogenicity is exploited to home a chemically supertoxic agent into tumor cells, while administration of unconjugated drug alone is not suitable due to its high toxicity. Therefore, ADCs can be further defined as prodrugs requiring the release of their toxic agent for their activation that commonly happens after ADC internalization into the target cell (1). From the standpoint of nanomedicine, the antibody in ADC structure acts as a self-targeting nanoscale carrier (1-3), thus, it could overcome the issues associated with nanomedicines based on synthetic nanomaterials such as cellular internalization, clearance, sterical hindering of binding to the epitopes and failing to release into targeted cells (4).

The first experimental design on ADC subject dates back to more than 50 years ago (5). However, the use of ADCs for cancer therapy has achieved considerable success in recent years after the introduction of four clinically approved ADCs such as Brentuximab vedotin (6,7), Trastuzumab emtansine (8-11), Inotuzumab ozogamicin (12) and Gemtuzumab ozogamicin (12,13) used for the treatment of patients with lymphoma (HL and ALL), HER2-positive, CD22-positive AML and CD33-positive ALL cancers, respectively. Likewise, a great deal of effort has also been made by the pharmaceutical companies to overcome the technological barriers associated with ADCs (14,15), whereby there are 160 ADCs undergoing preclinical trials (16) and 70 more under various stages of clinical evaluation (Table I).

Clinical efficacy of the ADCs arises following accurate selection of four parameters including tumor targeting, antibody, cytotoxic payload, and method of antibody linkage to the payload. The precise selection of each parameter can be achieved through the knowledge gained from the previous studies and established ADCs, and is discussed here.

Tumor markers in ADCs

The important aspects of tumor markers in ADCs are demonstrated in figure 2. An antigen with expression pattern slightly greater in tumor cells compared to healthy cells is sufficient to induce ADC activity. However, like other targeted drug delivery systems, the number of cell surface tumor markers can be a key determinant of ADC activity (17). The targets for ADC do not necessarily intervene in cell growth. ADCs tumor-suppressive function is mainly mediated through tumor marker potency for ADC internalization compared to the inhibition by blocking the cell growth (1,18-20). However, target biological roles such as those involved in cell division pathway (e.g. CD30 and CD70 tumor necrosis factor signaling) can be considered as an advantage for ADC efficacy. Accordingly, the currently employed targets and their biological roles are listed in table 1.

For instance, glembatumumab vedotin is an ADC against an extracellular domain of non-metastatic B melanoma-associated glycoprotein (GPNMB) that is aberrantly expressed in various carcinoma including hepatocellular (21), melanoma (22), gliomas (23), and two specitic breast cancer types, Basal-Like Breast Cancer (BLBC) and Triple Negative Breast Cancer (TNBC) (24). The GPNMB do not represent a high relative level of expression in all aforesaid carcinoma. One important property that may make GPNMB a potential therapeutic target for ADCs, originates from its biological role in MAPK/ERK pathway, as GPNMB expression can be upregulated by MAPK/ERK inhibitors (25).

From the structure standpoint, a relevant antigenic determinant on cell surface membranes, termed Extracellular Domain (ECD), is required as an immunizing agent for antibody generation (19). However, the potential of ECD to be shed into the circulation must be considered. The shed ECDs can potentially bind to ADC and consequently reduce the targeted delivery into the tumor cells (19).

A further concern in the selection of the target for ADC is related to the homogeneity or heterogeneity expression of the tumor marker on the tumor cell surface. Homogenous expression of the tumor targets has been demonstrated to be more in favor of ADC targeting than those expressed heterogeneously (26). However, heterogeneous antigen expression can particularly be beneficial for those ADCs that possess bystander killing activity (26-28). Bystander killing activity is referred to the potency of therapeutics delivery system in killing neighboring cells independently of targeted therapy assignment. This effect can be raised through reactive oxygen species or some cytotoxic metabolites that may be excreted from the tumor-targeted cells (26-29). As a result, recycling capability of a tumor marker would enhance bystander killing activity as it may promote leakage of ADC and metabolites to the neighboring cells. However, according to the reports, an extra recycling property is not desirable as in further Bystander activity (Ba), the greater side effects are predicted (30,31).

The promising future of the ADCs supports extensive studies to look for a potent ADC target with a wide range of expression, from earliest cell recognizable lineage to maturation. This represents an exquisitely selective target that covers all types of malignancies. CD19 is a good example of such target that is highly expressed in B-cell and the vast majority of Non-Flodgkin lymphomas (NHLs), and B-cell Acute Lymphoid Leukemia (B-ALL) (99%) (7,32-35). As shown in table 1, CD 19 has been marked as a target to produce ADCs, including SAR3419 (7,32,35), SGN-CD19A (32), MDX-1206 (36), and ADCT-402 (33).

Antibodies in ADCs

Antibody component in ADCs undertakes both roles including being a carrier and targeting agent. The main aspects of the antibody in ADCs are demonstrated in figure 3. High specificity of targeting and minimal immunogenicity are the main characteristics for Ab component in ADCs. These prevent antibody cross reactions to other antigens, avoiding both toxicity and removal/elimination of the ADC before reaching to the tumor. The high affinity of the Ab for efficient uptake into target cells is another important factor in ADC design (30,54-56). To the best of our knowledge, there is no substantial report about optimal or even minimum required binding affinity (Kd) of antibody component. In figure 4, a binding affinity less than 10 nM (Kd<10 nM) is commonly needed for the Ab component and accordingly for an effective ADC, based on frequency distribution histogram. The affinity of the antibody to its immunogen can affect the property of antibody which is termed as receptor-mediated antibody internalization. Receptor-mediated antibody internalization is a key mechanism underlying antibody endocytosis that is induced through antibody binding to its specific antigen (77). It has been reported that, alternative antibodies against the same immunogen can exhibit different rates of internalization (19). Rapid internalization can raise both ADC efficacy and safety simultaneously, since it reduces the opportunity of the ADC for offtarget release (1,98).

In addition to rapid internalization as a prerequisite for an antibody, the route by which antibody is internalized should be also considered, because it can potentially influence ADC processing (99). For instance, Clathrin-coated Pit-mediated receptor internalization (caveolae pathway), at least in some cases, has been reported to traffic ADC to the cells. In caveolae pathway, ADC is directed to the Golgi or endoplasmic reticulum (Non-proteolytic compartments) instead of endosomes or lysosomes (Proteolytic compartment of the cells) (118). ADC's traffic to the non-proteolytic compartments may impede its proteolytic process to release effective metabolites (6). Antibody capability to induce receptor mediated internalization is somewhat a mandatory requirement in design of new generation of ADCs. Antibody with low intefnalization rate has no desired therapeutics index even for the tumors expressing high levels of surface antigen (99). To compensate inefficient internalizing of ADC, a much more potent drug and high stable linkage chemistry (linkage between the antibody and drug moiety) are required that would be discussed in next sections.

Optimal pharmacokinetic (PK) properties including longer half-life is another aspect of the antibody component in ADC design (30,54,55). It has been reported that Ab with longer half-life show high elimination and rapid clearance of the ADC in plasma (136). As shown in table 1, it is not compulsory for a mAb itself to represent therapeutic activity in the ADC. However, therapeutic activity of the mAb is a desirable property besides killing activity mediated by the cytotoxic payload (137,138).

Antibody therapeutic activity is usually mediated via immune-mediated effector functions such as Antibody-Dependent Cellular Cytotoxicity (ADCC), Antibody-Dependent Cellular Phagocytosis (ADCP), Complement Dependent Cytotoxicity (CDC), and cytokine signaling modulation in terms of inhibition or induction (Table 1). Such therapeutic activities can be further employed to design ADCs with enhanced cell killing activity (8-11,43,120-123). According to the obtained data in table 1, isotype 1 immunoglobulin (IgGl) seems to be prone to induce immunotherapeutic activity.

In this regard, many attempts have been made to engineer mAbs with therapeutic activity. For instance, the Fc domain affinity of anti-CD 19 targeting antibodies for the Fc[gamma]RIII has been enhanced, either by Fc glycolengineering approaches, e.g. MEDI-55 (150) and MDX-1342 (151) or amino acid substitution, e.g. XmAb5574 (152) and XmAb 5871 or MOR-208 (31,153). Such modification resulted in an increase of ADCC activity in antibody. To the best of our knowledge, the above engineered antibodies have not been used for designing ADCs yet. However, there are some reports of ADCs which have employed a combination/fusion of two engineered antibody fragments. Such fusion antibodies are termed as bispecific Antibody (bsAb), while ADCs designed from the bsAbs were named bispecific ADC (bsADC) (154). Blinatumomab and AFM11 are typical bispecific antibodies, two fusions of anti-CD 19 scFv and anti-CD3 scFv, which were engineered to enhance CD19-positive cells killing activity through induction of T or NK cytotoxic immune effector cells (35,155). A derivative of blinatumomab has been also constructed to induce the controlled T cell activation, named ZW38 (156). The ZW38 was conjugated to a microtubule cytotoxic agent for the preparation of a novel class of bsADC capable of mediating T cell cytotoxicity (156). Another bsADC, B10v5x225-H-vc-MMAE (Monomethyl auristatin E-MMAE), has been recently developed to simultaneously target EGFR and c-MET which are two tyrosine kinases receptors correlated with tumor growth and metastasis (157,158). B10v5x225-H-vc-MMAE contains a bsAb from fusion of anti c-MET Fab fragment and anti-EGFR scFv that was engineered to represent low affinity to EGFR which is a ubiquitous tissue antigen (157). The side effect of B10v5x225-H-vc-MMAE can be avoided to some extent due to attenuated affinity toward EGFR receptors in healthy ceils (157). Bridging a rapidly internalizing protein with a tumor specific marker is also another recent method to construct bsAb, e.g., anti HER2 crosslink to prolactin cytoplasmic domain receptor (159) with the ability to improve internalization and cell killing activity of the bsADC.

Cytotoxic payloads in ADCs

Briefly, cytotoxic payloads for new generation of ADCs should meet many of the criteria as outlined in figure 5. Antibody component in ADCs is incapable of carrying a large number of cytotoxic payload due to its structure. Therefore, the cytotoxic payload in the new generation of ADCs must be highly super-toxic to eradicate majority of the tumor cells even with minimal payload delivery (160). The rate of mAb uptake by tumor cells is approximately less than 0.003-0.08% of injected dose per gram in a tumor (54,55). Furthermore, low expression and poor internalizing activity of the most tumor-associated antigens can cause negligible ADC delivery to the tumor target cells. Hence, ADCs equipped with highly super-cytotoxic payload are imperative, because they must show therapeutic effect while having limited release. According to the reports, a highly cytotoxic agent should exhibit an IC50 of about 10 nM or less obtained from an examination with KB cells upon a 24-hr exposure time (30,54,55,161). A highly super cytotoxic payload can be originated from plant, animal or microorganisms; in this regard, the most important issue can be the finding of cytotoxic payloads with negligible immunogenic potential in the body. In new generation of ADCs, such cytotoxic payloads are likely to be chemical anti-cancer drugs since experimental evidence confirmed that they are less immunogenic than glycol/peptide cytotoxic agents when circulating in the blood. Some anticancer drugs such as doxorubicin (DOX), mitoxantrone, and etoposide are impaired under hypoxic condition: a condition appeared in solid cancer cell population (162,163). Hence, needless to say, those drugs may not be considered as cytotoxic payloads.

Taking a look at current cytotoxic drugs (Table 1) shows that they generally affect DNA synthesis or cell division to block cell proliferation (mitosis) (38.98). Monomethyl auristatin derivatives which bind to tubulin and are able to inhibit microtubule assembly/polymerization (IC50=10-500 pM) (32) are the most commonly used cytotoxic drugs in ADC design with approximately 50% share of the field (Table 1). Maytansinoids derivatives (~30%)), pyrrolobenzodiaze-pine (~7%), camptothecin analogs (~6%), n-acetyl-[gamma]-calicheamicin (4%), duocarmycin (DUO) (~3%) and doxorubicin (~1%) are the other abundant cytotoxic payloads (Table 1). The above cytotoxic compounds are 100 to 10000 folds more potent in vitro than typical chemotherapeutic agents and are chosen based on their different actions on cancer and noncancerous cells. DNA modulators have significant effects on malignant cells as they are divided more rapidly than normal cells (163).

Furthermore, a cytotoxic agent of the ADC is better to be studied in an in vitro condition to determine whether it is a substrate, inhibitor or inducer of metabolizing enzymes (e.g., cytochrome P-450 isozymes (CYPs), and some transporter enzymes like P-glycoprotein) (98). Such studies help to elucidate the in vivo factors that may be contributed to the elimination/enhancement of the cytotoxic agent (27,98,164). New studies to introduce new payloads focused on agents against Tumor-Initiating Cells (TICs) (27,164). Such payloads assist to widen the target area and to circumvent potential resistance of cancer cells. Pyrrolobenzodiazepines (PBDs), derivatives of naturally occurring tricyclic antibiotics, duocarmycins, anthracyclines, a-amanitin (a bicyclic octapeptide from the fungus Amanita), and topoisomerase inhibitors including SN-38 are categorized as TIC payloads (1,164).

Rovalpituzumab tesirine is one example of ADC with PBD as a payload (Table 1), that has been reported to have a potency to eliminate pulmonary neuroendocrine TICs at subpicomolar level in vivo (83).

The cytotoxic payload should be also stable during preparation or storage and circulation in the blood. Cytotoxic payloads that are not fully stable can potentially be converted to undesirable drug forms during conjugation or storage. Solubility of the cytotoxic agent in aqueous solution is another important criterion in ADC design. Antibody is considered a protein and its conjugation to the cytotoxic agent must be performed in aqueous solutions with minimal organic cosolvents (163.165). Extreme hydrophobicity of payload can potentially change antibodies biological properties, resulting in hydrophobic aggregation of the antibody either during conjugation process or storage (163). The hydrophilicity of cytotoxic payloads will affect cell membrane permeability of parent ADC or its metabolites which may also be beneficial in term of bystander activity (17,26,163,166). However, the ability of cytotoxic payloads to form hydrophobic metabolite after intercellular cleavage of ADC is preferable since the metabolites with more hydrophobic group show better blood clearance and safety (165). According to the reports, about 95-99% of ADC molecules are metabolized before binding to tumor cells (160). This may raise safety concern as it can enhance the potential cytotoxic side effects of ADC. Thereby, the use of cytotoxic payloads with well-characterized metabolite profiles can be an advantage to enhance ADC safety in particular (1,2,167-169).

Cytotoxic payload should present a dominant functional group suitable for linkage to the antibody component of ADC (34). If a dominant functional group does not exist on the cytotoxic agent, at least, it should be amenable to modification, in which a desired substituent is introduced on appropriate sites (170).

The copy number and heterogeneity of antigen expression are the other important issues that must be considered in the selection of cytotoxic agent (30,31). More expression of target antigen may be a reason to apply a cytotoxic agent with low potency. Typically, payloads that promote the bystander effect in cancer cells are more desirable to design ADCs directed for the antigens expressed heterogeneously (26).

The ability to choose specified cytotoxic payloads with mechanism of action compatible with standard of care has been reported to facilitate clinical success of the ADCs in biopharmaceutical market. For instance, microtubule disrupting payloads are commonly chemotherapeutic drugs that are used for the treatment of cancers, including breast, ovarian and prostate cancer (54,55) (Table 1). Both availability in the market and reasonable cost can be alternative rationale for choosing a cytotoxic payload in ADC design (1).

Linking cytotoxic payloads to antibodies in ADCs

One of the dynamic research fields in ADC design is the study of the methods that are correlated with antibody conjugation to cytotoxic payloads, as it has a great role on balancing between ADC therapeutic efficacy and toxicity (30,31,54). The key concerns in linkage chemistry are demonstrated in figure 6. Conjugation site on antibody component, a well-defined Drug to Antibody Ratio (DAR), homogeneity and linkage stability are the important parameters that need to be considered in conjugation.

In general, interchain disulfide bridges and surface-exposed lysines are the most currently used residues on the antibody for conjugation to cytotoxic payloads, respectively (>50 vs. >30%) (Table 1). Hydroxyl groups on carbohydrate structures are the other residues in antibodies that have been rarely used as conjugation sites for ADC (The schematic linkage in figure 6 is an example of this strategy) (1,171).

Theoretically, the linkage of cytotoxic payloads to the surface-exposed lysine of mAb occurs after reduction of ~40 lysine residues on both heavy and light chain of mAb (172) and it results in 0-8 cytotoxic payload linkages per antibody and heterogeneity with about one million different ADC species (30,173). Cysteine conjugation occurs after reduction of four interchain disulfide bonds and results in eight exposed sulfhydryl groups. Linking drugs per antibody can differ from zero to 8 molecules, generating a heterogeneous population of ADC (Greater than one hundred different ADC species) (30).

Due to low stability and safety properties of the pharmaceutical products with heterogeneous contents, they are complex to be accurately predicted in terms of efficacy or therapeutic window (27,30). Therefore, improvement of conjugation methods to achieve homogeneous ADC is very crucial.

In this case, it is possible to reduce just two of four interchain mAb's disulfide bonds of cysteine residues through carefully mild reduction conditions, as interchain disulfide bridges are more prone to reduction than intrachain disulfide bridges (171,174,175). However, such mild reduction is not easily possible in practice and a diverse number of cysteines may be reduced (0-4), resulting in a heterogeneous mixture of ADC (30,173). Hence, the production of homogeneous ADCs through payload conjugation with native residues can be laborious. To overcome this limitation, many site-specific conjugation approaches have been developed, in which a known number of cytotoxic payloads are constantly conjugated to defined sites on mAbs. Some of the approaches are explained below:

I. A conjugation through engineered cysteine residues that neither damages antibody fab region nor interferes with Fc-mediated effector functions, called THIOMAB technology (173,176). In THIOMAB technology, the heavy chain alanine 114 is substituted with two or more reactive cysteine residues at a predefined site for conjugation with cytotoxic payload (173). Anti-TENB2 ADC is an example that is prepared by THIOMAB technology and is currently in phase I trial (Table 1).

2. Re-engineering of mAb is able to incorporate with unnatural amino acids, e.g. selenocysteine (177), acetylphenylalanine (178), and para-azidomethyl-1- phenylalanine (42).

3. Site-specific enzyme-mediated conjugation to genetically engineered antibody is as follows:

Incorporating a thiolated sugar analogue, 6-thiofucose, to the antibody carbohydrate that introduces new chemically active thiol groups using fucosyltransferase VIII (179)

Providing a ketone reactive group on antibody glycosylation site by glycotransferases (180),

Introducing an aldehyde reactive group on the antibody using sialyltransferase (181) or formylglycine-generating enzyme (182),

Genetically introducing specific glutamine tags to antibody whereby payloads with a primary amine group can be linked to the [gamma]-carbonyl amide group of glutamine tags. Such reaction is catalyzed by a microbial transglutaminase which is capable of recognizing glutamines tags from naturally glutamines residues (73,183-185),

Providing LPXTG tagged antibodies (A penta-peptide as a substrate for transpeptidation reaction) as specific linkage sites for the oligo-glycine-containing payloads, which are mediated by Staphylococcus aureus Sortase A enzyme (186),

Conjugation of phosphopantetheine-linked payloads to the serine residues of the peptide-tagged antibodies via phosphopantetheinyl transferases catalysis (187),

4. Chemoenzymatic site direct conjugation, e.g., providing two azide groups at asparagine 297 (Asn-297) residue in antibody constant region (Fc) is linked with cytotoxic payloads using copper-mediated click reaction (188). The azide functional groups are formed in a selective hydrolysis reaction that is mediated by an Endo-beta-N-acetylglucosaminidase (EndoS) chemoenzyme.

ADC as a potential targeted delivery system must be passed through all hurdles, including blood circulation, antigen binding, internalization, payload release, and eventual payload action. An unstable linkage can lead to premature release of the payload, before reaching the site of action (98). Therefore, reasonable chemical stability must be considered in the design of chemical linkage between cytotoxic payload and-antibody.

Although a direct linkage between cytotoxic and antibody components has generally shown more stability in circulation (1,98), conjugation reactions are mostly created with linkers in comparison with direct linkage between cytotoxic and antibody component (Table 1). The choice of proper linkers has been discussed in the related publications devoted to the progress of ADCs (30,31,54,189.190). As shown in table 1, about 50% of the ADCs are using Valine-Citrulline peptidyl (VC) linker. N-succinimidyl 4-(2-pyridyldithio) butyrate (SPDB) (18%), acid-labile hydrazine (10%), maleimidomethyl cyclohexane-1-carboxylate (MCC), maleimidocaproyl (MC) (10%), N-succinimidyl 4-(2-pyridyldithio pentanoate (SPP) and carbonate (3%) linkers are other employed linkers.

Limited drug-linker designs for more than 70 current ADC clinical trials (Table 1) are a dilemma regarding linkage chemistry that may restrict simultaneous development of ADCs against both hematological and solid tumors. Generally, the properties of linkers can be altered by the cytotoxic payload release mechanism (191). Cytotoxic payload in ADC technology must be released into the cell to exert its therapeutic activity, thus ADC linkers should be chosen based on their stability to keep ADC intact during circulation and capable of cleaving inside the targeted cell (191,192). Linker stability is defined based on lack/low level of cleaving agents (e.g., protease or reductive agents) in the bloodstream compared to the cytoplasm (163).

The current linkers used in ADCs are also broadly classified as cleavable and noncleavable linkers based on where they are cleaved into the cytoplasm. Cleavable linkers are those containing a conditional cleavage sites sensitive to be cleaved immediately after ADC internalization, such as VC, SPDB, SPP, and hydrazine which can be triggered through protease reactions, glutathione reduction, and acidic pH, respectively (163,164).

Noncleavable linkers are stable from early to late endosome transition and their cytotoxic partner is just released by degradation of antibody in lysosomes, e.g. MCC and MC linkers that link Ab to the payload via thioether linkage (190).

Characteristics of ADC target such as copy number, internalization rate and level of homogeneity should be considered in conjugation method and linker selection. For instance, ADC with disulfide-linkage has been shown to have more cytotoxic activity than the same ADC with thioether linkage when they were directed to the tumor cell lines expressing a low copy number of targeted antigen (17).

Cleavable linkers may increase the possibility of bystander effect (27). Hence, it is logical to use cleavable linkers in designing ADCs directed for the antigen that is heterogeneously expressed in tumors (26).

In vivo adverse effects of ADCs are infiuenced by the use of cleavable or noncleavable linkers. As in the case of tubulin inhibitor payloads, which is linked through cleavable linkers to the antibody component, e.g. SPDB-DM4 (Ravtansine-DM4), or VC-MMAE, peripheral neuropathy can be frequently observed, whereas noncleavable linkers often trigger hematological toxicity, possibly due to an increased dose and interactions with Fc[gamma] receptors on hematopoietic cells (164).

The type of linker plays an important role in ADC catabolite products with regard to processing into targeted cells or metabolizing by clearance mechanisms. The type of ADC catabolites may influence some ADC features such as IC50, Maximum Tolerated Dose (MTD) (192,193), and kill Multidrug Resistance (MDR) expressing cells (192,194).

Conclusion

ADC is considered exciting and promising antibody-based therapeutics to improve cancer therapy. Growth in the number of registered ADCs in clinical trials (Table 1) represents the pharmaceutical industry interest in investment for research and development in the field, as it has been stated by others (14,15).

The design of an ADC might seem to be not very complex, while several issues must be taken into consideration to complete ADC's potential as a therapeutic agent for cancer. This might be the main reason for the condition that small number of ADCs have reached the market (Table 1). The major issues associated with the development of ADCs seem to be originated from the factors that interfere with ADCs efficacy and off-target cytotoxicity. The precise selection of all four parameters, i.e. tumor marker, antibody, cytotoxic payload, and linkage strategy would be required to prepare a successful ADC.

With regard to ADC tumor markers, they do not have to be involved in tumor growth (1,18,20,31). Therefore, ADC can present therapeutic application in a broad range of tumors. However, an ADC tumor marker should meet at least three criteria of considerable expression level in tumor cells vs. normal cells, presenting cell surface immunogen, and being capable of performing ADC internalization.

High specificity, adequate affinity, and receptor-mediated internalization are the major aspects of antibody choice. Efforts to optimize antibody component would be a great idea to translate into improved ADCs. In fact, some major ADCs' weaknesses including, low efficiency (156), low internalization (159), off-target effect due to the target expression in normal tissues (157), and heterogeneity expression of the target in the tumors can be overcome via antibody improvement. Antibody engineering technology for production of alternative bsAbs to design more efficient ADCs (bsADCs) has been proven in several preclinical models (156,157,159). The rationale behind this technology is the fact that the aforesaid ADC's weaknesses can be solved through ADC designs (bsADCs) operating from improved antibody (bsAb) in terms of affinity, specificity, internalization activity, by enhancing the therapeutic activity or decreasing ADC's side effects.

Another main concern in the development of ADCs is related to the study of finding cytotoxic payloads that are potent enough with contined DAR (Up to 7 drugs per antibody) (195) to exert therapeutic activity. Having reasonable aqueous solubility, non-immunogenic, as well as stability in storage and bloodstream is a common criterion for choosing cytotoxic payloads.

In contrast, the introduction of innovative methods to modify ADCs cytotoxic payloads with versatile functional groups (e.g. thiol, amine groups) is the other interesting subject, as it eases the conjugation process. One further challenge of ADCs is associated with the limitation of linkage and conjugation chemistry to link an optimized number of the payloads to the antibody in predefined location homogeneously.

Interdisciplinary and multidisciplinary works and related studies such as recombinant DNA technology, bioconjugation, and chemistry are the hopeful strategies to get the purpose of achievement in site-specific conjugation and homogeneous ADCs (73,173,176-187,196,197).

Based on promising reports from research to synthesize homogeneous ADCs, it is likely that the first ADC products constructed using site-specific conjugation will be made for cancer therapy that may hold the promise about the future use of ADCs.

Taken together, despite challenges in ADC design, the future of ADCs seems to be much promising as more clinical trials and basic researches conducted on existing ADCs would pave the way to tackle issues regarding tumor marker, antibody, cytotoxic payload, and linkage strategy.

Acknowledgement

This review study was supported as a Ph.D., program by a grant from Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS) (grant no. 92-03-159-25467). We further acknowledge the numerous labs, authors, and publications that we were unable to cite in this review due to space restrictions.

Conflict of Interest

The authors declare that they have no competing interests.

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Mohammad-Reza Nejadmoghaddam (1,2), Arash Minai-Tehrani (2), Ramin Ghahremanzadeh (2), Morteza Mahmoudi (1), Rassoul Dinarvand (1,3*), and Amir-Hassan Zarnani (4,5,6*)

(1.) Nanotechnotogy Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

(2.) Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran

(3.) Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

(4.) Department of Immunology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran

(5.) Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran

(6.) Immunology Research Center, Iran University of Medical Sciences, IUMS, Tehran, Iran

(*) Corresponding authors:

Rassoul Dinarvand, Pharm D., PhD., Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Amir-Hassan Zarnani, D.M.T., Ph.D., Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran

Tel: +98 21 64121014, 22432020

Fax: +98 21 66959052, 22432021

E-mail: dinaruand@tums.ac.ir, zarnania@gmail.com

Received: 29 Oct 2017

Accepted: 31 Dec 2017
Table 1. Current ADCs in clinical development based on targeting
antigens with an overview of their properties

ADC names                       Clinical phase, indication

Targeting HER2 antigen, a transmembrane RTKs in the growth of some
cancer cells:
Kadcyla,                        Approved in 2013, for
Ado-Trastuzumab                 treatment of her2 positive
emtansine, T-DMI                breast cancer
SYD985,                         Phase I, for treatment of
Trastuzumab vc-                 USC and epithelial EOC
seco-DUBA                       Phase I, for treatment of low
ADC XMT-1522                    HER+ breast, gastric and
                                lung cancers
                                Phase I, for treatment of low
ADC ARX788                      HER+ breast, ovarian, lung
                                and gastric cancers
                                Phase I, for treatment of low
                                HER2+ expressing breast,
ADC ADCT-502                    NSCLC, gastroesophageal,
                                bladder cancer
Targeting EGFR antigen, a RTKs that is essential for ductal and
lobuloalveolar development:
ABT-414,                        Phase II, for treatment of
Depatuxizumab
mafodotin                       GBM
                                Phase I, for treatment of
AMG 595
                                GBM
IMGN289,
Laprituximab                    Phase I, for treatment of
emtansine                       NSCLC and HNSCC
ABBV-221                        Phase I, for treatment of solid
                                tumor
Targeting CD70 (CD27L) antigen a TP2 and member of the tumor necrosis
factor family:
                                Phase I, for treatment of
SGN-75                          CD70-positive NEIL and
                                metastatic RCC
MDX-1203. BMS-                  Phase I, for treatment of
936561                          ccRCC or B-NHL
SGN-CD70A                       Phase I, for treatment of
                                RCC, MCLD, LBC, PL,
                                Phase I, for treatment of
AMG 172                         ccRCC
Targeting CD33 antigen, a EGP:
Mylotarg,                       Withdrawn 2010 and approved
Gemtuzumab                      in 2017, for treatment
Ozogamicin (GO)                 of [CD33.sup.+] AML
SGN-CD33A                       Phase I, for treatment of
                                AML
                                Phase I, for treatment of
AVE9633                         AML
Targeting CD19 antigen, a TPI on B cells as an accessory molecule
for B-cell signal transduction and TAA:
SAR34I9,                        Phase II, for treatment of B-NHL
coltuximab                      and B-ALL Phase I, for treatment of
ravtansine                      B-Cell Malignancies
SGN-CD19A                       Phase I, for treatment of
ADCT-402                        relapsed or refractory B-ALL
Targeting Mesothelin
antigen, a
glycophosphatidyl
inositol anchored
protein:
BAY 94-9343,                    Phase II, for treatment of
anetumab ravtansine             MPM
                                Phase I & II, for treatment of
BMS-986148                      Mesothelin -expressing cancers
DMOT4039A                       Phase I, for treatment of
                                pancreatic and P-OC
Targeting CD22 antigen, a transmembrane sialoglycoprotein functions as
an inhibitory receptor for BCR signaling and BCR-induced cell death:
Inotuzumab, IO,
Ozogamicin, CMC-                Approved in 2017, for treatment
544                             of [CD22.sup.+] ALL
Pinatuzumab
vedotin,                        Phase II, for treatment of
DCDT2980S,                      NHL and CLL
RG7593
Targeting CEACAM5 antigen, labetuzumab, CEA, CD66e, a EGP that has a
role in cell adhesion and invasion:
IMMU-130,
hMN14-SN38,
labetuzumab                     Phase II, for treatment of
                                mCRC
govitecan,
labetuzumab-SN-38
                                Phase I & II, for treatment of
SAR40870
                                B-Cell Malignancies
Targeting Trop-2 (MIS), TACSTD2 or GA733-1) antigen, a EGP transduces
calcium signal has a role in ERK1/2 MAPK pathway which mediates cancer
cell proliferation, migration, invasion, and survival:
IMMU-132, hrS7-                 Phase III, for treatment of
SN-38, Sacituzumab              pancreatic cancers, SCLC
govitecan                       and TNBC
PF-06664178, Trop-              Phase I, for treatment of OC,
2 ADC, RN927C                   NSCLC and breast cancer
Targeting PSMA antigen, a TP2 has known enzymatic activities and acts
as a glutamate-preferring
carboxypeptidase:
                                Phase I & II, for treatment of
PSMA ADC                        prostate cancer
                                Phase I & II, for treatment of
MLN2704                         prostate cancer
Targeting CD37 (Tetra spanin-26) antigen, a  TP3 present on mature B
cells, implicates as a signaling death receptor to regulate B/T-cell
interactions/proliferation:
1MGN529,                        Phase I or II, for treatment of
Naratuximab
emtansine                       BCL,CLL, NHL
                                Phase I, trial for treatment of
AGS67E                          NHL. DLBCL with high
                                level of CD37 expression
Targeting CD30 (TNFRSF8) antigen, a tumor necrosis factor:
Adcetris,                       Approved in 2011, for
brentuximab
vedotin, SGN-35                 treatment of HL and ALL.
Targeting HER3 antigen, a member of EGFR family RTK, frequently
overexpressed in solid tumors, including breast, lung, and colorectal
tumors of epithelial origin; it has no active kinase domain itself but
is activated through heterodimerization with other members of the EGFR
family:
                                Phase I & II, for treatment of
U3-1402                         HER3-positive metastatic
                                breast cancer
Targeting DLL3 antigen, scr-like kinase (Fyn3) acts as a notch ligand
for cell-cell communication:
Rovalpituzumab                  Phase I & II, for treatment of
tesirine, Rova-T,               SCLC
SC16LD6.5
Targeting GPNMB antigen, an EGP is involved in differentiation of
osteoblasts, and cellular adhesion:
Glembatumumab                   Phase II, for treatment of
Vedotin (GV),
CDX-011,CR011-                  GPNMB-positive breast and
vcMMAE                          melanoma cancer
Targeting CD79b antigen, a TP1 on B cells mediates signal transduction
cascade activated by BCR:
Polatuzumab                     Phase II, for treatment of
vedotin, RG7596,
DCDS4501A                       NHLs and CLLs
Targeting GCC antigen, a part of calcium negative fccdback system and
has a role in cGMP synthesizes from GTP:
Indusatumab
vedotin,                        Phase II, for treatment of GI
MLN0264,TAK-                    malignancies
264, 5F9-VCMMAE
Targeting NaPi2b antigen, a sodium phosphate transporter:
Lifastuzumab
vedotin, RG7599,                Phase II, for treatment of
DN1B0600A                       NSCLC and ovarian cancer
Targeting CA6 antigen, a sialoglycotopeof MUC-1 is over-expressed in
variety of solid tumors, including breast, ovarian, cervical, lung and
pancreatic tumors:
                                Phase II, for treatment of
SAR566658                       OC, breast, cervical, lung
                                cancers
Targeting CD74 antigen, a TP2 on B cells involved in the formation and
transport of MHC class II protein:
Milatuzumab-                    Phase I & II, for treatment of
doxorubicin,                    MM
IMMU-110, hLLl-DOX
Targeting CD138 antigen, syndecanl, a type I transmembrane heparan
sulfate proteoglycan participates in cell proliferation, cell migration
and cell-matrix interactions:
BT-062,
Indatuximab                     Phase I & II, for treatment of
ravtansine                      MM
Targeting BCMA antigen, a receptor for a proliferation-inducing ligand
and B-cell activating factor:
GSK2857916                      Phase I, for treatment of MM
Targeting specific myeloma antigen:
DFRF4539A,
RG7598                          Phase I, for treatment of MM
Targeting SLAMF7(CSI) antigen:
ABBV-838                        Phase I, for treatment of MM
Targeting CD56 antigen, associates with FGFR and stimulates RTKs to
induce neurite outgrowth:
IMGN901,
Lorvotuzumab                    Phase I & II, for treatment of
mertansine,                     CD56+ MM
huN901-DM1/BB-10901
Targeting ENPP3 (CD203c) antigen, a TP2 belongs to a series of
ectoenzymes, possess ATPase and ATP pyrophosphatase activities:
                                Phase I & II, for treatment of
AGS-16C3F                       RRCC
Targeting TF(CD142) antigen, a TP and initiator of the coagulation
cascade:
Humax-TF-ADC,                   Phase I & II, for treatment of
tisotumab vedotin               Multiple solid tumours
Targeting TIM1 antigen, a member of the T cell transmembrane IgG and
mucin family, which plays critical roles in regulating immune cell
activity especially regarding the host response to viral infection:
CDX-014                         Phase I & II, for treatment of
                                RCC
Targeting FOLR1 antigen, a membrane-bound protein regulates transport
of the vitamin B9 into cells:
                                Phase I, for treatment of
IMGN853,                        folate receptor alpha
mirvetuximab                    (FR[alpha])-positive cancer, e.g.,
soravtansine                    relapsed EOC
Targeting MUCI6 (CA-125) antigen, a member of the mucin family GP that
acts as a lubricating barrier against foreign particles and infectious
agents on the apical membrane of epithelial cells:
RG7458,
Sofituzumab                     Phase I, for treatment of
Vedotin,                        ovarian and pancreatic cancer
DMUC5754A
Targeting CanAg antigen, is a novel glycoform of mucin family GP:
IMGN242, HuC242-                Phase I, for treatment of
DM4, cantuzumab                 Non-colorectal and Pancreatic Cancer
ravtansine
Targeting Ckit(CD117 or SCFR) antigen, a TP and RTKs having a key role
in the regulation of cell differentiation and proliferation:
LOP628, Anti c-KIT              Phase I, for treatment of
ADC                             AML and solid tumors
Targeting EphA2 antigen, belonging to ephrin receptor subfamily of the
RTKs family regulating cell migration, adhesion, proliferation
and differentiation:
                                Phase I, for treatment of
MEDI-S47, MI-                   relapsed or refractory solid
CP177                           tumors associated with
                                EphA2 expression
Targeting Nectin 4 (PVRL4) antigen, a TP1 and member of a family of
cellular adhesion molecules, involved in Ca2+-independent cellular
adhesion:
ASG-22ME, AGS-                  Phase I, for treatment of
22M6E, anti-nectin-             MUC
4 ADC, Enfortumab
vedotin
Targeting SLTRK6 antigen, belonging to the integral TPs(SLITRK) with
LRR:
AGS15E,anti-                    Phase I, for treatment of
SLITRK6 ADC                     MUC
Targeting HGFR (cMet) antigen, RTKs for hepatocyte growth factor:
ABBV-399,
Telisotuzumab                   Phase I, for treatment of
vedotin                         c-Met-expressing NSCLC
Targeting FGFR2 antigen, type 2 RTKs with a role in both embryonic
development and tissue repair:
BAY1187982, anti-               Phase I, for treatment of
FGFR2 ADC,                      FGFR2-positive human
Aprutumab ixadotin              malignancies
Targeting C4.4a (LYPD3) and uPAR antigen, glycosylphosphatidylinositol
(GPI)-anchored proteins:
BAYI 129980,
Lupartumab                      Phase I, for treatment of
amadotin, anti-                 LSCC
C4.4a ADC
Targeting p-Cadherin (Cadherin 3) antigen, a cell-surface protein and
member of the cadherin family plays a role in cell adhesion, motility,
invasion, and proliferation:
                                Phase I, for treatment of
PCA062                          TNBC; head and neck &
                                esophageal cancers
Targeting 5T4 (TPBG) antigen, a EGP correlated with increased
invasiveness:
                                Phase I, for treatment of lung
PF-06263507, anti-              and breast cancer with 5T4
5T4 ADC                         expression
Targeting STEAPI antigen, cell-surface protein is predominantly
expressed in prostate tissue:
RG7450,
DSTP3086S,
Vandortuzumab                   Phase I, for treatment of
vedotin, STEAPI                 mCRPC
ADC
Targeting PTK7 antigen, RTKs 7 presents on TICs in the Wnt signaling
pathway:
PF-06647020,
h6M24-vc0101,                   Phase I, for treatment of
PTK7-targeted                   NSCLC, TNBC and OC
ADC
Targeting Ephrin-A4 (EFNA4) antigen, RTKs modulate signaling pathways
that impact cell fate decisions during embryogenesis and adult tissue
homeostasis:
                                Phase I, for treatment of
PF-06647263                     TNBC and OC
Targeting LIV1(SLC39A6 or ZIP6) antigen, a member of the zinc
transporter family playing a key role in tumor cell progression and
metastasis:
SGN-LIVIA,                      Phase I, for treatment of
anti-LIV-1                      metastatic breast,
Targeting TENB2 antigen, a prostate cancer target associated with the
progression of poorly differentiated and androgen-independent tumor
types:
Anti-TENB2 ADC                  Phase I, for treatment of
                                prostate cancer
Targeting ETBR antigen, a G-protein coupled receptor that can activate
RAF/MEK signaling:
RG7636,                         Phase I, for treatment of
DEDN-6526A                      melanoma
Targeting integrin
v3 antigen:
                                Phase I, for treatment of
IMGN-388
                                NSCLC and prostate cancer
Targeting crypto antigen, belonging to the EGF-CFC family of growth
factor-like molecules, playing a key role in signaling pathways of
certain transforming growth factor-beta super-family members:
                                Phase I, for treatment of
BIIB-015                        breast, ovary, stomacr, lung,
                                and pancreas Cripto-expressing
                                tumor cells
Targeting AGS-5 (SLC44A4) antigen, a sodium-dependent transmembrane
transport protein:
                                Phase I, for treatment of
ASG-5ME                         pancreatic, prostate and
                                gastric cancers
Targeting LY6E antigen, an interferon (IFN)-inducible
glycosylphosphatidyl inositol (GPI)-linked cell membrane protein:
                                Phase I, for treatment of
RG7841,                         HER2- breast cancer and
DLYE5953A                       NSCLC
Targeting AXL (UFO) antigen, a member of the TAM (TYRO3, AXL and MER)
family of RTK, playing a key role in tumor cell proliferation,
survival, invasion and metastasis:
HuMax-Axl-ADC                   Phase I, for treatment of
                                multiple solid tumors
Targeting CD205 antigen, a type I C-type lectin receptor normally
expressed on various APC and some leukocyte sub-populations:
MEN1309/OBT076                  Phase I, for treatment of
                                NHL
Targeting CD25 (IL-2 Ralpha) antigen, a TP and tumor-associated antigen
(TAA), expressed on certain cancer cells:
ADCT-301,anti-                  Phase I, for treatment of
                                AML, ALL, relapsed HL and
CD25-PBD ADC                    NHL with CD25-positive
Targeting LAMP-1 antigen, playing a key role in cell-cell adhesion and
migration:
                                Phase I, for treatment of
SAR428926                       HER2 negative breast expansion
                                in LAMP-1 positive
                                TNBC
Targeting MN/CA IX antigen, a TGP expressed in some human carcinomas
and appears to be involved in cancer cell proliferation and
transformation:
ADC BAY79-4620,                 n/a
MN-IC

ADC names                       Ab, kd, therapeutics
                                activity                     Payload

Targeting HER2 antigen, a transmembrane RTKs in the growth of some
cancer cells:
Kadcyla,                        huIgG1 (trastuzumab),
                                n/a, ADCC and
Ado-Trastuzumab                 HER2-dependent PI3K/AKT      DMI
emtansine, T-DMI                signaling
SYD985,                         huIgG2 ami HER2
Trastuzumab vc-                 (Trastuzumab), n/a, no       DUO
seco-DUBA
ADC XMT-1522                    huIgGlanti-HER2(HT-          AF-HPA
                                19), n/a, n/a
ADC ARX788                      IgGlanti-HER2, n/a, n/a      MMAF
                                huIgGlanti-HER2
ADC ADCT-502                    (trastuzumab)                PBD
Targeting EGFR antigen, a RTKs that is essential for ductal and
lobuloalveolar development:
ABT-414,                        huIgGI anti EGFR
Depatuxizumab                   (ABT-806), 0.06 nM,          MMAF
mafodotin                       inhibits EGFR signaling
                                huIgGlanti-EGFRvllI,
AMG 595                                                      DMI
                                0.61 nM, n/a
IMGN289,
Laprituximab                    huIgG anti-EGFR              DMI
emtansine                       (J2898A), n/a, n/a
ABBV-221                        huIgGI anti-EGFR, n/a,       MMAE
                                n/a
Targeting CD70 (CD27L) antigen a TP2 and member of the tumor necrosis
factor family:
SGN-75                          hu anti-CD70(hIF6),
MDX-1203. BMS-                  n/a, n/a                     MMAF
                                hu anti-CD70, n/a, n/a       DUO
936561
SGN-CD70A                       hu anti-CD70, n/a, n/a       PBD
AMG 172                         huIgG 1, n/a, n/a            DMI
Targeting CD33 antigen, a EGP:
Mylotarg,
Gemtuzumab                      huIgG4, n/a, n/a             Calich.
Ozogamicin (GO)
SGN-CD33A                       hu anti-CD33 with            PBD
                                engineered cysteines,
                                n/a, n/a
AVE9633                         anti-CD33,n/a, n/a           DM4
Targeting CD19 antigen, a TPI on B cells as an accessory molecule
for B-cell signal transduction and TAA:
SAR34I9,                        huIgG1 anti-CD 19
coltuximab                                                   DM4
ravtansine                      (huB4), n/a, ADCC
                                huIgG1 anti-CD19
SGN-CD19A                       (hBUI2), n/a, ADCC           MMAF
ADCT-402                        huIgG1anti-CD19, n/a,        PBD
                                n/a
Targeting Mesothelin antigen, a glycophosphatidyl inositol anchored
protein:
BAY 94-9343,                    hu anti-mesothelin, n/a,
anetumab ravtansine             n/a                          DM4
BMS-986148                      anti mesothelin              n/a
DMOT4039A                       hu anti-mesothelin           MMAE
                                (7D9.V3), n/a, n/a
Targeting CD22 antigen, a transmembrane sialoglycoprotein functions as
an inhibitory receptor for BCR signaling and BCR-induced cell death:
Inotuzumab, IO,
Ozogamicin, CMC-                huIgG4 anti                  Calich.
544                             CD29(G544),n/a, no
Pinatuzumab
vedotin,                        huIgG1anti-CD22
DCDT2980S,                      (Epratuzumab), n/a, n/a      MMAE
RG7593
Targeting CEACAM5 antigen, labetuzumab, CEA, CD66e, a EGP that has a
role in cell adhesion and invasion:
IMMU-130,
hMN14-SN38,                     huIgG1 anti-CEACAMS
labetuzumab                     (hMNI4), 1.5 nM,             SN-38
govitecan,                      ADCC
labetuzumab-SN-38
                                huIgG1 anti-CEACAM5,
SAR40870                        n/a, n/a                     DM4
Targeting Trop-2 (MIS), TACSTD2 or GA733-1) antigen, a EGP transduces
calcium signal has a role in ERK1/2 MAPK pathway which mediates cancer
cell proliferation, migration, invasion, and survival:
IMMU-132, hrS7-                 huIgG1 anti-trop-2 (RS7
SN-38, Sacituzumab              or Sacituzumab), 0.564       SN-38
govitecan                       nM, ADCC
PF-06664178, Trop-              Engineered huIgG 1 anti-     PF063801
2 ADC, RN927C                   Trop-2, 14 nM, n/a           01
Targeting PSMA antigen, a TP2 has known enzymatic activities and acts
as a glutamate-preferring carboxypeptidase:
PSMA ADC                        hu anti-PSMA, 35.6-          MMAE
                                46.5 nM, n/a
                                hu anti-PSMA (huJ591),
MLN2704                         n/a, n/a                     DMI
Targeting CD37 (Tetra spanin-26) antigen, a  TP3 present on mature B
cells, implicates as a signaling death receptor to regulate B/T-cell
interactions/proliferation:
1MGN529,                        huIgGlanti-CD37
Naratuximab                     (K7153A), n/a, ADCC          DM1
emtansine                       and CDC,
                                huIgG2[kappa] anti-CD37
AGS67E                          (AGS67C or vCD37-            MMAE
                                9a73), n/a, n/a
Targeting CD30 (TNFRSF8) antigen, a tumor necrosis factor:
Adcetris,                       Chimeric IgGlanti-           MMAE
brentuximab                     CD30(cAC10 or
vedotin, SGN-35                 SGN30), n/a.
Targeting HER3 antigen, a member of EGFR family RTK, frequently
overexpressed in solid tumors, including breast, lung, and colorectal
tumors of epithelial origin; it has no active kinase domain itself but
is activated through heterodimerization with other members of the EGFR
family:
U3-1402                         huIgGlanti-                  DXd
                                HER3(Patritumab)
Targeting DLL3 antigen, scr-like kinase (Fyn3) acts as a notch ligand
for cell-cell communication:
Rovalpituzumab                  huIgG1 anti-DLL3
tesirine, Rova-T,               antibody (SC-16), 2.6        PBD
SC16LD6.5                       nM, n/a
Targeting GPNMB antigen, an EGP is involved in differentiation of
osteoblasts, and cellular adhesion:
Glembatumumab
Vedotin (GV),
CDX-011,CR011-                  huIgG2(CR011), n/a, no       MMAE
vcMMAE
Targeting CD79b antigen, a TP1 on B cells mediates signal transduction
cascade activated by BCR:
Polatuzumab
vedotin, RG7596,                anti-CD79b, n/a, n/a         MMAE
DCDS4501A
Targeting GCC antigen, a part of calcium negative fccdback system and
has a role in cGMP synthesizes from GTP:
Indusatumab
vedotin,                        IgGlanti-GCC(TAK-            MMAE
MLN0264,TAK-                    264), n/a, n/a
264, 5F9-VCMMAE
Targeting NaPi2b antigen, a sodium phosphate transporter:
Lifastuzumab                    huIgG1 anti-NaPi2b,
vedotin, RG7599,                                             MMAE
DN1B0600A                       10.19 nM,n/a
Targeting CA6 antigen, a sialoglycotopeof MUC-1 is over-expressed in
variety of solid tumors, including breast, ovarian, cervical, lung and
pancreatic tumors:
SAR566658                       huIgG1 anti-CA6              DM4
                                (huDS6 IgGl),n/a. n/a
Targeting CD74 antigen, a TP2 on B cells involved in the formation and
transport of MHC class II protein:
Milatuzumab-                    hu anti-CD74                 DOX
doxorubicin,
IMMU-110, hLLl-DOX
Targeting CD138 antigen, syndecanl, a type I transmembrane heparan
sulfate proteoglycan participates in cell proliferation, cell migration
and cell -matrix interactions:
BT-062,
Indatuximab                     Chimeric anti-CDI38          DM4
ravtansine                      (nBT062), n/a, n/a
Targeting BCMA antigen, a receptor for a proliferation-inducing ligand
and B-cell activating factor:
                                Engineered
GSK2857916                      afucosylated huIgG1
                                anti-BCMA, I nM,             MMAF
                                ADCC
Targeting specific myeloma antigen:
DFRF4539A,
RG7598                          n/a, n/a, n/a                MMAE
Targeting SLAMF7(CSI) antigen:
                                huIgGl anti-SLAMF7,
ABBV-838                                                     MMAE
                                n/a,n/a
Targeting CD56 antigen, associates with FGFR and stimulates RTKs to
induce neurite outgrowth:
IMGN901,                        huIgGl anti-CD56
Lorvotuzumab                    (Lorvotuzuniab or
mertansine,                     N901), 0.002 nM,             DMI
huN901-DM1/BB-10901
Targeting ENPP3 (CD203c) antigen, a TP2 belongs to a series of
ectoenzymes, possess ATPase and ATP pyrophosphatase activities:
                                huIgG2k anti-ENPP3
AGS-16C3F                       (AGS16-7.8), 0.3-1.1         MMAF
                                nM, no
Targeting TF(CD142) antigen, a TP and initiator of the coagulation
cascade:
Humax-TF-ADC,                   IgG1 anti-TF                 MMAE
tisotumab vedotin
Targeting TIM1 antigen, a member of the T cell transmembrane IgG and
mucin family, which plays critical roles in regulating immune cell
activity especially regarding the host response to viral infection:
CDX-014                         huIgGlanti-TIM1              MMAE
Targeting FOLR1 antigen, a membrane -bound protein regulates transport
of the vitamin B9 into cells:
IMGN853,
mirvetuximab                    FR[alpha]-binding antibody   DM4
soravtansine
Targeting MUCI6 (CA-125) antigen, a member of the mucin family GP that
acts as a lubricating barrier against foreign particles and infectious
agents on the apical membrane of epithelial cells:
RG7458,                                                      MMAE
Sofituzumab                     IgGlanti-MUC16               and
Vedotin,                        (OC125), n/a, n/a            MMAF
DMUC5754A
Targeting CanAg antigen, is a novel glycoform of mucin family GP:
IMGN242, HuC242-                hu anti-CanAg (C242 or       DM4
DM4, cantuzumab                 cantuzumab), n/a, n/a
ravtansine
Targeting Ckit(CD117 or SCFR) antigen, a TP and RTKs having a key role
in the regulation of cell differentiation and proliferation:
LOP628, Anti c-KIT              huIgGlanti-(c-Kit), n/a,
ADC                             n/a                          DMI
Targeting EphA2 antigen, belonging to ephrin receptor subfamily of the
RTKs family regulating cell migration, adhesion, proliferation and
differentiation:
MEDI-S47, MI-                   huIgGl anti-EphA2
                                (ICI), InM, n/a              MMAF
CP177
Targeting Nectin 4 (PVRL4) antigen, a TP1 and member of a family of
cellular adhesion molecules, involved in Ca2+- independent cellular
adhesion:
ASG-22ME, AGS-                  huIgGl anti-nectin-4
22M6E, anti-nectin-             (AGS-22M6)0.01 nM,           MMAE
4 ADC, Enfortumab
vedotin                         n/a
Targeting SLTRK6 antigen, belonging to the integral TPs(SLITRK) with
LRR:
AGS15E,anti-                    huIgG2[gamma] anti-SLITRK6,  MMAE
SLITRK6 ADC                     n/a, n/a
Targeting HGFR (cMet) antigen, RTKs for hepatocyte growth factor:
                                Engineered huIgG1
                                without the agonist
ABBV-399,                       activity associated with
Telisotuzumab                   c-Met (ABT-700), 0.2 to      MMAE
vedotin                         1.5 nM ADCC and
                                c-Met inhibition &
                                downstream signaling
                                molecules
Targeting FGFR2 antigen, type 2 RTKs with a role in both embryonic
development and tissue repair:
BAY1187982, anti-               huIgG1 anti-FGFR2
                                isoforms FGFR2-IIIb
FGFR2 ADC,                      and FGFR2-11IC (BAY          MMAE
Aprutumab ixadotin              1179470), 75 nM n/a
Targeting C4.4a (LYPD3) and uPAR antigen, glycosylphosphatidylinositol
(GPI)-anchored proteins:
BAYI 129980,
Lupartumab                      huIgG1 anti-C4.4A, 60        MMAE
amadotin, anti-                 nM, n/a
C4.4a ADC
Targeting p-Cadherin (Cadherin 3) antigen, a cell-surface protein and
member of the cadherin family plays a role in cell adhesion, motility,
invasion, and proliferation:
PCA062                          IgG1 anti-P-cadherin,        DM1
                                n/a, n/a
Targeting 5T4 (TPBG) antigen, a EGP correlated with increased
invasiveness:
PF-06263507, anti-              huIgG1 anti-5T4              MMAF
5T4 ADC
Targeting STEAPI antigen, cell-surface protein is predominantly
expressed in prostate tissue:
RG7450,
DSTP3086S,                      huIgG1 anti-TEAP1
Vandortuzumab                   (MSTP2109A),                 MMAE
vedotin, STEAPI                 2.4 nM, n/a
ADC
Targeting PTK7 antigen, RTKs 7 presents on TICs in the Wnt signaling
pathway:
PF-06647020,
h6M24-vc0101,                   huIgGlanti-PTK7
PTK7-targeted                   (h6M24) 0.002 nM, n/a        Aur0101
ADC
Targeting Ephrin-A4 (EFNA4) antigen, RTKs modulate signaling pathways
that impact cell fate decisions during embryogenesis and adult tissue
homeostasis:
                                huIgG1 anti-Ephrin-A4
PF-06647263                     (E32), n/a, n/a              Calich.
Targeting LIV1(SLC39A6 or ZIP6) antigen, a member of the zinc
transporter family playing a key role in tumor cell progression and
metastasis:
                                huIgG1 anti-LIV1
SGN-LIVIA,                      (hLlV22),4.6 nM,             MMAE
anti-LIV-1                      n/a
Targeting TENB2 antigen, a prostate cancer target associated with the
progression of poorly differentiated and androgen-independent tumor
types:
                                ThioMab version of the
Anti-TENB2 ADC                  anti-TENB2 antibody          MMAE
                                (Prl),2.3 nM/,n/a
Targeting ETBR antigen, a G-protein coupled receptor that can activate
RAF/MEK signaling:
RG7636,                         huIgG1 anti-ETBR, n/a,
DEDN-6526A                      n/a                          MMAE
Targeting integrin
v3 antigen:
IMGN-388                        huIgGlanti-Integrin v3       DM4
Targeting crypto antigen, belonging to the EGF-CFC family of growth
factor-like molecules, playing a key role in signaling pathways of
certain transforming growth factor-beta super- family members:
BIIB-015                        huIgG1 anti-Cripto           DM4
                                (BI1B015), n/a, n/a
Targeting AGS-5 (SLC44A4)
antigen, a sodium
-dependent transmembrane
transport protein:
ASG-5ME                         huIgG2 anti-AGS-5, n/a,      MMAE
                                na
Targeting LY6E antigen, an interferon (IFN)- inducible
glycosylphosphatidyl inositol (GPI)-linked cell membrane protein:
RG7841,                         n/a, n/a, n/a                MMAE
DLYE5953A
Targeting AXL (UFO) antigen, a member of the TAM (TYRO3, AXL and MER)
family of RTK, playing a key role in tumor cell proliferation,
survival, invasion and metastasis:
                                huIgGlanti-AXL, n/a,
HuMax-Axl-ADC                                                MMAE
                                n/a
Targeting CD205 antigen, a type I C-type lectin receptor normally
expressed on various APC and some leukocyte sub-populations:
                                huIgGl anti-CD205,
MEN1309/OBT076                                               DM4
                                n/a, n/a
Targeting CD25 (IL-2 Ralpha) antigen, a TP and tumor-associated antigen
(TAA), expressed on certain cancer cells:
ADCT-301,anti-                  huIgG1 against CD25,
                                                            PBD
CD25-PBD ADC                    n/a, n/a
Targeting LAMP-1 antigen, playing a key role in cell-cell adhesion and
migration:
SAR428926                       huIg Glanti-                 DM4
                                LAMPl(Ab-l)
Targeting MN/CA IX antigen, a TGP expressed in some human carcinomas
and appears to be involved in cancer cell proliferation and
transformation:
ADC BAY79-4620,                 huIgGl anti-MN/CA IX,
                                                             MMAE
MN-IC                           n/a, ADCC

ADC names                       Linkage strategy

Targeting HER2 antigen, a transmembrane RTKs in the growth of some
cancer cells:
Kadcyla,                        Native lysine residues,
Ado-Trastuzumab                 SMCC nonreducible
emtansine, T-DMI                thioether linkage
SYD985,
Trastuzumab vc-                 VC-seco
seco-DUBA
ADC XMT-1522                    Fleximer[R]
                                pAcF site-specific
ADC ARX788                      oxime linkage, AS269
                                noncleavable linker
ADC ADCT-502                    Cysteine residues, VA-PABC
Targeting EGFR antigen, a RTKs that is essential for ductal and
lobuloalveolar development:
ABT-414,                        Native cysteine residues,
Depatuxizumab                   MC noncleavable
mafodotin                       linker
                                Native lysine residues,
AMG 595                         SMCC noncleavable
                                thioether linker
IMGN289,                        Native lysine residues,
Laprituximab                    SMCC noncleavable
emtansine                       thioether linker
ABBV-221                        VC protease-cleavable
                                linker
Targeting CD70 (CD27L) antigen a TP2 and member of the tumor necrosis
factor family:
                                Native cysteine residues,
SGN-75                          MC noncleavable
                                linker
MDX-1203. BMS-                  Native cysteine residues,
936561                          VC protease-cleavable linker
SGN-CD70A                       VA linker
                                Native lysine residues,
AMG 172                         MCC noncleavable
                                linker
Targeting CD33 antigen, a EGP:
Mylotarg,                       Native lysine residues,
Gemtuzumab                      (AcBut)-N-acyl acidlabile
Ozogamicin (GO)                 hydrazone linker
SGN-CD33A                       Engineered cysteine
                                residues, VA linker
                                Native lysine residues,
AVE9633                         SPDB disulfide cleavable
                                linker
Targeting CD19 antigen, a TPI on B cells as an accessory molecule for
B-cell signal transduction and TAA:
SAR34I9,                        Native lysine residues,
coltuximab                      SPDB disulfide cleavable
ravtansine                      linker
                                Native cysteine residues,
SGN-CD19A                       MC linker,
                                noncleavable
                                Native cysteine residues,
ADCT-402                        VA and maleimide cleavable
                                linker
Targeting Mesothelin antigen, a glycophosphatidyl inositol anchored
protein:
BAY 94-9343,                    Lysine residues, SPDB
anetumab ravtansine             disulfide cleavable
                                linker
BMS-986148                      n/a
DMOT4039A                       A noncleavable alkyl
                                hydrazide linker
Targeting CD22 antigen, a transmembrane sialoglycoprotein functions as
an inhibitory receptor for BCR signaling and BCR -induced cell death:
Inotuzumab, IO,                 Native lysine residues,
Ozogamicin, CMC-                (AcBut)-N-acyl,
544                             Acid-labile hydrazone
                                linker
Pinatuzumab                     Native cysteines restdues,
vedotin,                        MC-VC-PAB
DCDT2980S,                      linker
RG7593
Targeting CEACAM5 antigen, labetuzumab, CEA, CD66e, a EGP that has a
role in cell adhesion and invasion:
IMMU-130,                       Native cysteine residues,
hMN14-SN38,                     CL2A pH sensitive
labetuzumab                     (Benzylcarbonate
govitecan,                      site) carbonate linker
labetuzumab-SN-38
                                Lysine residues, SPDB
SAR40870                        disulfide cleavable
                                linker
Targeting Trop-2 (MIS), TACSTD2 or GA733-1) antigen, a EGP transduces
calcium signal has a role in ERK1/2 MAPK pathway which mediates cancer
cell proliferation, migration, invasion, and survival:
IMMU-132, hrS7-                 Native cysteine residues,
SN-38, Sacituzumab              CL2A pH sensitive
govitecan                       carbonate link
                                Site-specific
PF-06664178, Trop-              transglutaminase tag,
2 ADC, RN927C                   AcLys-VC-PABC
                                linker
Targeting PSMA antigen, a TP2 has known enzymatic activities and acts
as a glutamate-preferring carboxypeptidase:
                                Native cysteine residues,
PSMA ADC                        VC protease-cleavable
                                linker
                                Lysine residues, SPP
MLN2704                         disulfide cleavable
Targeting CD37 (Tetra spanin-26) antigen, a TP3 present on mature B
cells, implicates as a signaling death receptor to regulate B/T-cell
interactions /proliferation:
1MGN529,                        Native lysine residues,
Naratuximab                     SMCC nonreducible
emtansine                       thioether linkage
                                Native cysteines residues,
AGS67E                          VC protease-cleavable
                                linker
Targeting CD30 (TNFRSF8) antigen, a tumor necrosis factor:
Adcetris,                       Native interchain cysteine,
brentuximab                     MC-VC- PABC
vedotin, SGN-35                 linker
Targeting HER3 antigen, a member of EGFR family RTK, frequently
overexpressed in solid tumors, including breast, lung, and colorectal
tumors of epithelial origin; it has no active kinase domain itself but
is activated through heterodimerization with other members of the EGFR
family:
U3-1402                         n/a
Targeting DLL3 antigen, scr-like kinase (Fyn3) acts as a notch ligand
for cell-cell communication:
Rovalpituzumab                  Native interchain cysteine,
                                PEG8[??] va linker,
tesirine, Rova-T,               cathepsin-B cleavable
SC16LD6.5                       dipeptide linker
Targeting GPNMB antigen, an EGP is involved in differentiation of
osteoblasts, and cellular adhesion:
Glembatumumab                   Cysteine residues, VC
Vedotin (GV),
CDX-011,CR011-                  protease-cleavable
vcMMAE                          linker
Targeting CD79b antigen, a TP1 on B cells mediates signal transduction
cascade activated by BCR:
Polatuzumab                     Native cysteine residues,
vedotin, RG7596,                VC protease-cleavable
DCDS4501A                       linker
Targeting GCC antigen, a part of calcium negative fccdback system and
has a role in cGMP synthesizes from GTP:
Indusatumab                     Native cysteine residues,
vedotin,                        VC protease-cleavable
MLN0264,TAK-                    linker
264, 5F9-VCMMAE
Targeting NaPi2b antigen, a sodium phosphate transporter:
Lifastuzumab                    Native cysteine residues,
vedotin, RG7599,                VC protease-cleavable
DN1B0600A                       linker
Targeting CA6 antigen, a sialoglycotopeof MUC-1 is over-expressed in
variety of solid tumors, including breast, ovarian, cervical, lung and
pancreatic tumors:
                                Native lysine residues,
SAR566658                       SPDB disulfide cleavable
                                linker
Targeting CD74 antigen, a TP2 on B cells involved in the formation and
transport of MHC class II protein:
Milatuzumab-                    Native lysine residues,
doxorubicin,                    Acid-labile hydrazone
IMMU-110, hLLl-                 linker
DOX
Targeting CD138 antigen, syndecanl, a type I transmembrane heparan
sulfate proteoglycan participates in cell proliferation, cell migration
and cell -matrix interactions:
BT-062,                         Native lysine residues,
Indatuximab                     SPDB disulfide cleavable
ravtansine                      linker
Targeting BCMA antigen, a receptor for a proliferation-inducing ligand
and B-cell activating factor:
                                Native cysteine residues,
GSK2857916                      MC noncleavable
                                linker
Targeting specific myeloma antigen:
DFRF4539A,
RG7598                          n/a
Targeting SLAMF7(CSI) antigen:
                                Native cysteine residues,
ABBV-838                        VC protease-cleavable
                                linker
Targeting CD56 antigen, associates with FGFR and stimulates RTKs to
induce neurite outgrowth:
IMGN901,
Lorvotuzumab                    Lysine residues, SPP
mertansine,                     disulfide cleavable
huN901-DM1/BB-                  linker
10901
Targeting ENPP3 (CD203c) antigen, a TP2 belongs to a series of
ectoenzymes, possess ATPase and ATP pyrophosphatase activities:
                                Native cysteine
AGS-16C3F                       residues, MC
                                noncleavable linker
Targeting TF(CD142) antigen, a TP and initiator of the coagulation
cascade:
Humax-TF-ADC,                   Native cysteine residues,
tisotumab vedotin               VC protease-cleavable linker
Targeting TIM1 antigen, a member of the T cell transmembrane IgG and
mucin family, which plays critical roles in regulating immune cell
activity especially regarding the host response to viral infection:
                                Native cysteine
CDX-014                         residues, VC protease-cleavable linker
Targeting FOLR1 antigen, a membrane -bound protein regulates transport
of the vitamin B9 into cells:
IMGN853,                        Native lysine residues,
mirvetuximab                    Sulfo- SPDB disulfide
soravtansine                    cleavable linker
Targeting MUCI6 (CA-125) antigen, a member of the mucin family GP that
acts as a lubricating barrier against foreign particles and infectious
agents on the apical membrane of epithelial cells:
RG7458,                         Native cysteine
Sofituzumab                     residues, MC-VC-PABC
Vedotin,                        linker
DMUC5754A
Targeting CanAg antigen, is a novel glycoform of mucin family GP:
IMGN242, HuC242-                Native lysine residues,
DM4, cantuzumab                 SPDB disulfide
ravtansine                      cleavable linker
Targeting Ckit(CD117 or SCFR) antigen, a TP and RTKs having a key role
in the regulation of cell differentiation and proliferation:
LOP628, Anti c-KIT              Native lysine residues,
ADC                             SMCC noncleavable
                                thioether linker
Targeting EphA2 antigen, belonging to ephrin receptor subfamily of the
RTKs family regulating cell migration, adhesion, proliferation and
differentiation:
MEDI-S47, MI-                   Native cysteines residues, MC
CP177                           noncleavable linker
Targeting Nectin 4 (PVRL4) antigen, a TP1 and member of a family of
cellular adhesion molecules, involved in Ca2+- independent cellular
adhesion:
ASG-22ME, AGS-                  Native cysteines
22M6E, anti-nectin-             residues, VC protease-cleavable linker
4 ADC, Enfortumab
vedotin
Targeting SLTRK6 antigen, belonging to the integral TPs(SLITRK) with
LRR:

AGS15E,anti-                    Native cysteines residues, VC
SLITRK6 ADC                     protease-cleavable linker
Targeting HGFR (cMet) antigen, RTKs for hepatocyte growth factor:
ABBV-399,                       Native cysteines resi-dues,
Telisotuzumab                   VC protease-cleavable
vedotin                         linker
Targeting FGFR2 antigen, type 2 RTKs with a role in both embryonic
development and tissue repair:
BAY1187982, anti-              Lysine side chains and
FGFR2 ADC,                     a noncleavable linker
Aprutumab ixadotin
Targeting C4.4a (LYPD3) and uPAR antigen, glycosylphosphatidylinositol
(GPI)-anchored proteins:
BAYI 129980,                    Native cysteine residues,
Lupartumab                      noncleavable alkyl hydrazide linker
amadotin, anti-C4.4a ADC
Targeting p-Cadherin (Cadherin 3) antigen, a cell-surface protein and
member of the cadherin family plays a role in cell adhesion, motility,
invasion, and proliferation:
                                Native lysine residues,
PCA062                          SMCC noncleavable
                                thioether linker
Targeting 5T4 (TPBG) antigen, a EGP correlated with increased
invasiveness:
PF-06263507, anti-              Native cysteine residues, MC
5T4 ADC                         noncleavable linker
Targeting STEAPI antigen, cell-surface protein is predominantly
expressed in prostate tissue:
RG7450,
DSTP3086S,                      Native cysteine residues,
Vandortuzumab                   MC-vc-PAB
vedotin, STEAPI                 linker
ADC
Targeting PTK7 antigen, RTKs 7 presents on TICs in the Wnt signaling
pathway:
                                Transglutaminase tag
PF-06647020,                    (LLQGA) located
h6M24-vc0101,                   at the C-terminus of the
PTK7-targeted                   antibody heavy chain,
ADC                             cleavable
                                VC-PABC- linker
Targeting Ephrin-A4 (EFNA4) antigen, RTKs modulate signaling pathways
that impact cell fate decisions during embryogenesis and adult tissue
homeostasis:
                                Native lysine residues,
PF-06647263                     Flydrazone- CM1(Hydrazone acetyl
                                butyrate)
Targeting LIV1(SLC39A6 or ZIP6) antigen, a member of the zinc
transporter family playing a key role in tumor cell progression and
metastasis:
SGN-LIVIA,                      Native cysteine residues,
anti-LIV-1                       VC protease-cleavable linker
Targeting TENB2 antigen, a prostate cancer target associated with the
progression of poorly differentiated and androgen-independent tumor
types:
                                Native lysine residues,
Anti-TENB2 ADC                  protease-labile
                                VC-PABC- linker
Targeting ETBR antigen, a G-protein coupled receptor that can activate
RAF/MEK signaling:
RG7636,
DEDN-6526A                      n/a
Targeting integrin
v3 antigen:
                                Native lysine residues,
IMGN-388                        SPDB disulfide cleavable
                                linker
Targeting crypto antigen, belonging to the EGF-CFC family of growth
factor-like molecules, playing a key role in signaling pathways of
certain transforming growth factor-beta super-family members:
                                Native lysine residues,
BIIB-015                        SPDB disulfide cleavable linker
Targeting AGS-5 (SLC44A4) antigen, a sodium -dependent transmembrane
transport protein:
ASG-5ME                         Native cysteine residues, VC
                                protease-cleavable linker
Targeting LY6E antigen, an interferon (IFN)- inducible
glycosylphosphatidyl inositol (GPI)-linked cell membrane protein:
RG7841,                         Native cysteine residues, VC
DLYE5953A                       protease-cleavable linker
Targeting AXL (UFO) antigen, a member of the TAM (TYRO3, AXL and MER)
family of RTK, playing a key role in tumor cell proliferation,
survival, invasion and metastasis:
HuMax-Axl-ADC                   Native cysteine residues, VC
                                protease-cleavable linker
Targeting CD205 antigen, a type I C-type lectin receptor normally
expressed on various APC and some leukocyte sub-populations:
                                Native lysine residues,
MEN1309/OBT076                  SPDB disulfide cleavable linker
Targeting CD25 (IL-2 Ralpha) antigen, a TP and tumor-associated antigen
(TAA), expressed on certain cancer cells:
ADCT-301,anti-                  Cleavable linker
CD25-PBD ADC
Targeting LAMP-1 antigen, playing a key role in cell-cell adhesion and
migration:
SAR428926                       Lysine residues, SPDB
Targeting MN/CA IX antigen, a TGP expressed in some human carcinomas
and appears to be involved in cancer cell proliferation and
transformation:
ADC BAY79-4620,                 Native cysteine residues,
MN-IC                           VC protease-cleavable linker

                                DAR, MTD,
ADC names                       bystander effect

Targeting HER2 antigen, a transmembrane RTKs in the growth of some
cancer cells:
Kadcyla,
Ado-Trastuzumab                 ~3.5, 3.6 mg/kg, no
emtansine, T-DMI
SYD985,
Trastuzumab vc-                 ~2.8, 1.88 mg/kg, yes
seco-DUBA
ADC XMT-1522                    12, n/a, yes
ADC ARX788                      2, n/a, n/a
ADC ADCT-502                    1.7, n/a, n/a
Targeting EGFR antigen, a RTKs that is essential for ductal and
lobuloalveolar development:
ABT-414,
Depatuxizumab                   ~3.8,1.5 mg/kg, no
mafodotin
AMG 595                         ~3.5, n/a, no
IMGN289,
Laprituximab                    n/a, n/a, no
emtansine
ABBV-221                        n/a, n/a, n/a
Targeting CD70 (CD27L) antigen a TP2 and member of the tumor necrosis
factor family:
SGN-75                          n/a, 3, n/a
MDX-1203. BMS-                  n/a, 15 mg/kg, yes
936561
SGN-CD70A                       n/a, n/a, yes
AMG 172                         n/a, n/a, no
Targeting CD33 antigen, a EGP:
Mylotarg,
Gemtuzumab                      n/a, 0,25 mg/kg, yes
Ozogamicin (GO)
SGN-CD33A                       n/a, n/a, yes
                                n/a, n/a, n/a
AVE9633
Targeting CD19 antigen, a TPI on B cells as an accessory molecule for
B-cell signal transduction and TAA:
SAR34I9,
coltuximab                      ~3.5, ~4.3 mg/kg, yes
ravtansine
SGN-CD19A                       n/a, 6.0, no
ADCT-402                        n/a, n/a, n/a
Targeting Mesothelin antigen, a glycophosphatidyl inositol anchored
protein:
BAY 94-9343,
anetumab ravtansine             n/a, 6.5 mg/kg, yes
BMS-986148                      n/a, n/a, n/a
DMOT4039A                       ~3.5, 2.4 mg/kg, n/a
Targeting CD22 antigen, a transmembrane sialoglycoprotein functions as
an inhibitory receptor for BCR signaling and BCR -induced cell death:
Inotuzumab, IO,
Ozogamicin, CMC-544             n/a, 0.05 mg/kg, yes
Pinatuzumab
vedotin,
DCDT2980S,                      - 2.4, 2.4 mg/kg, yes
RG7593
Targeting CEACAM5 antigen, labetuzumab, CEA, CD66e, a EGP that has a
role in cell adhesion and invasion:
IMMU-130,
hMN14-SN38,
labetuzumab                     7-8, 6-10 mg/kg, yes
govitecan,
labetuzumab-SN-38
SAR40870                        n/a, n/a, yes
Targeting Trop-2 (MIS), TACSTD2 or GA733-1) antigen, a EGP transduces
calcium signal has a role in ERK1/2 MAPK pathway which mediates cancer
cell proliferation, migration, invasion, and survival:
IMMU-132, hrS7-                 ~7.6, 8-10 mg/kg, yes
SN-38, Sacituzumab
govitecan
PF-06664178, Trop-              2.0, n/a, n/a
2 ADC, RN927C
Targeting PSMA antigen, a TP2 has known enzymatic activities and acts
as a glutamate-preferring carboxypeptidase:
PSMA ADC                        n/a, 2.5 mg/kg, yes
MLN2704                         n/a, 60 mg'kg, yes
Targeting CD37 (Tetra
spanin-26) antigen, a
TP3 present on mature B cells, implicates as a signaling death receptor
to regulate B/T-cell interactions /proliferation:
1MGN529,
Naratuximab                     n/a, 1.0 mg/kg, no
emtansine
AGS67E                          n/a, 1.2 mg/kg, yes
Targeting CD30 (TNFRSF8) antigen, a tumor necrosis factor:
Adcetris,
brentuximab                     ~4, 1.8 mg/kg, yes
vedotin, SGN-35
Targeting HER3 antigen, a member of EGFR family RTK, frequently
overexpressed in solid tumors, including breast, lung, and colorectal
tumors of epithelial origin; it has no active kinase domain itself but
is activated through heterodimerization with other members of the EGFR
family:
U3-1402                         ~8, n/a, n/a
Targeting DLL3 antigen, scr-like kinase (Fyn3) acts as a notch ligand
for cell-cell communication:
Rovalpituzumab
tesirine, Rova-T,               ~ 2, 0.2 mg kg, yes
SC16LD6.5
Targeting GPNMB antigen, an EGP is involved in differentiation of
osteoblasts, and cellular adhesion:
Glembatumumab
Vedotin (GV),
CDX-011,CR011-                  -4.5, 1.9 mg/kg, yes
vcMMAE
Targeting CD79b antigen, a TP1 on B cells mediates signal transduction
cascade activated by BCR:
Polatuzumab
vedotin, RG7596,                n/a, 2.4 mg/kg, yes
DCDS4501A
Targeting GCC antigen, a part of calcium negative fccdback system and
has a role in cGMP synthesizes from GTP:
Indusatumab
vedotin,                        n/a,~1.8 mg/kg,yes
MLN0264,TAK-264,
5F9-VCMMAE
Targeting NaPi2b antigen, a sodium phosphate transporter:
Lifastuzumab
vedotin, RG7599,                n/a, 2.4 mg/kg, yes
DN1B0600A
Targeting CA6 antigen, a sialoglycotopeof MUC-1 is over-expressed in
variety of solid tumors, including breast, ovarian, cervical, lung and
pancreatic tumors:
SAR566658                       6.5 mg/kg
Targeting CD74 antigen, a TP2 on B cells involved in the formation and
transport of MHC class II protein:
Milatuzumab-doxorubicin,        n/a, n/a, yes
IMMU-110, hLLl-DOX
Targeting CD138 antigen, syndecanl, a type I transmembrane heparan
sulfate proteoglycan participates in cell proliferation, cell migration
and cell -matrix interactions:
BT-062,
Indatuximab                     n/a, 2.7 mg/kg, yes
ravtansine
Targeting BCMA antigen, a receptor for a proliferation-inducing ligand
and B-cell activating factor:
GSK2857916                      n/a, n/a, no
Targeting specific myeloma antigen:
DFRF4539A,
RG7598                          n/a, n/a, n/a
Targeting SLAMF7(CSI) antigen:
ABBV-838                        n/a, n/a, n/a
Targeting CD56 antigen, associates with FGFR and stimulates RTKs to
induce neurite outgrowth:
IMGN901,
Lorvotuzumab
mertansine,                     3.7,2 .0 mg/kg, n/a
huN901-DM1/BB-10901
Targeting ENPP3 (CD203c) antigen, a TP2 belongs to a series of
ectoenzymes, possess ATPase and ATP pyrophosphatase activities:
AGS-16C3F                       ~4, 1.8 mg/kg, no
Targeting TF(CD142) antigen, a TP and initiator of the coagulation
cascade:
Humax-TF-ADC,                   n/a, 1.8 mg/kg,yes
tisotumab vedotin
Targeting TIM1 antigen, a member of the T cell transmembrane IgG and
mucin family, which plays critical roles in regulating immune cell
activity especially regarding the host response to viral infection:
CDX-014                         n/a, n/a, n/a
Targeting FOLR1 antigen, a membrane -bound protein regulates transport
of the vitamin B9 into cells:
IMGN853,
mirvetuximab                    n/a, 6 mg/kg, yes
soravtansine
Targeting MUCI6 (CA-125) antigen, a member of the mucin family GP that
acts as a lubricating barrier against foreign particles and infectious
agents on the apical membrane of epithelial cells:
RG7458,
Sofituzumab                     n/a, 2.4 mg/kg, yes
Vedotin,
DMUC5754A
Targeting CanAg antigen, is a novel glycoform of mucin family GP:
IMGN242, HuC242-DM4,
cantuzumab                      n/a, n/a, yes
ravtansine
Targeting Ckit(CD117 or SCFR) antigen, a TP and RTKs having a key role
in the regulation of cell differentiation and proliferation:
LOP628, Anti c-KIT
ADC                             n/a, n/a, no
Targeting EphA2 antigen, belonging to ephrin receptor subfamily of the
RTKs family regulating cell migration, adhesion, proliferation and
differentiation:
MEDI-S47, MI-                   4, 6.0 mg/kg, no
CP177
Targeting Nectin 4 (PVRL4) antigen, a TP1 and member of a family of
cellular adhesion molecules, involved in Ca2+- independent cellular
adhesion:
ASG-22ME, AGS-22M6E,
anti-nectin-4                   n/a, 1-3 mg/kg, yes
ADC, Enfortumab
vedotin
Targeting SLTRK6 antigen, belonging to the integral TPs(SLITRK) with
LRR:
AGS15E,anti-                    n/a, n/a, yes
SLITRK6 ADC
Targeting HGFR (cMet) antigen, RTKs for hepatocyte growth factor:
ABBV-399,
Telisotuzumab                   ~3.1, 3 mg/kg, n/a
vedotin
Targeting FGFR2 antigen, type 2 RTKs with a role in both embryonic
development and tissue repair:
BAY1187982, anti-FGFR2
ADC,                            ~4, n/a, yes
Aprutumab ixadotin
Targeting C4.4a (LYPD3) and uPAR antigen, glycosylphosphatidylinositol
(GPI)-anchored proteins:
BAYI 129980,
Lupartumab                      ~4, 1.9 mg/kg, n/a
amadotin, anti-C4.4a ADC
Targeting p-Cadherin (Cadherin 3) antigen, a cell-surface protein and
member of the cadherin family plays a role in cell adhesion, motility,
invasion, and proliferation:
PCA062                          n/a, n/a, n/a
Targeting 5T4 (TPBG) antigen, a EGP correlated with increased
invasiveness:
PF-06263507, anti-              n/a,4.34 mg/kg, no
5T4 ADC
Targeting STEAPI antigen, cell-surface protein is predominantly
expressed in prostate tissue:
RG7450,
DSTP3086S,
Vandortuzumab                   1,8-2.0, 2.4 mg/kg,
vedotin, STEAPI                 yes
ADC
Targeting PTK7 antigen, RTKs 7 presents on TICs in the Wnt signaling
pathway:
PF-06647020,
h6M24-vc0101,
PTK7-targeted                   4, 1.5 mg/kg,yes
ADC
Targeting Ephrin-A4 (EFNA4) antigen, RTKs modulate signaling pathways
that impact cell fate decisions during embryogenesis and adult tissue
homeostasis:
PF-06647263                     4.6, - 0.08 mg/kg, yes
Targeting LIV1(SLC39A6 or ZIP6) antigen, a member of the zinc
transporter family playing a key role in tumor cell progression and
metastasis:
SGN-LIVIA,                      4, n/a, yes
anti-LIV-1
Targeting TENB2 antigen, a prostate cancer target associated with the
progression of poorly differentiated and androgen-independent tumor
types:
Anti-TENB2 ADC                  2, n/a, n/a
Targeting ETBR antigen, a G-protein coupled receptor that can activate
RAF/MEK signaling:
RG7636,
DEDN-6526A                      n/a, 2.4 mg/kg, n/a
Targeting integrin v3 antigen:
IMGN-388                        n/a, 3.5 mg/kg, n/a
Targeting crypto antigen, belonging to the EGF-CFC family of growth
factor-like molecules, playing a key role in signaling pathways of
certain transforming growth factor-beta super- family members:
BIIB-015                        n/a, n/a, n/a
Targeting AGS-5 (SLC44A4)
antigen, a sodium
-dependent transmembrane
transport protein:
ASG-5ME                         n/a, n/a, n/a
Targeting LY6E antigen, an interferon (IFN)- inducible
glycosylphosphatidyl inositol (GPI)-linked cell membrane protein:
RG7841,                         n/a, n/a, n/a
DLYE5953A
Targeting AXL (UFO) antigen, a member of the TAM (TYRO3, AXL and MER)
family of RTK, playing a key role in tumor cell proliferation,
survival, invasion and metastasis:
HuMax-Axl-ADC                   n/a, n/a, n/a
Targeting CD205 antigen, a type I C-type lectin receptor normally
expressed on various APC and some leukocyte sub-populations:
MEN1309/OBT076                  n/a, n/a, yes
Targeting CD25 (IL-2 Ralpha) antigen, a TP and tumor-associated antigen
(TAA), expressed on certain cancer cells:
ADCT-301,anti-                  n/a, n/a, n/a
CD25-PBD ADC
Targeting LAMP-1 antigen, playing a key role in cell-cell adhesion and
migration:
SAR428926                       n/a, n/a, n/a
Targeting MN/CA IX antigen, a TGP expressed in some human carcinomas
and appears to be involved in cancer cell proliferation and
transformation:
ADC BAY79-4620,                 n/a, n/a, n/a
MN-IC

                                Sponsor,
ADC names                       Reference

Targeting HER2 antigen, a transmembrane RTKs in the growth of some
cancer cells:
Kadcyla,                        Genentech, Inc.
Ado-Trastuzumab                 (8-11)
emtansine, T-DMI
SYD985,
Trastuzumab vc-                 Synthon BV
seco-DUBA                       (37-39)
                                Mersana
ADC XMT-1522                    Therapeutics
                                (40)
                                Zhejiang
ADC ARX788                      Medicine/Ambrx
                                (41)
                                ADC
ADC ADCT-502                    Therapeutics S.A.
                                (42)
Targeting EGFR antigen, a RTKs that is essential for ductal and
lobuloalveolar development:
ABT-414,                        Abbvie
Depatuxizumab
mafodotin                       (43)
                                Amgen
AMG 595
                                (44)
IMGN289,
Laprituximab                    ImmunoGen
emtansine                       (45)
ABBV-221                        Abbvie
                                (46)
Targeting CD70 (CD27L) antigen a TP2 and member of the tumor necrosis
factor family:
                                Seattle Genetics
SGN-75                          (47)
MDX-1203. BMS-                  Bristol-Myers
936561                          (48)
SGN-CD70A                       Seattle Genetics
                                (49)
                                Amgen
AMG 172                         (50)
Targeting CD33 antigen, a EGP:
Mylotarg,
Gemtuzumab                      Pifizer
Ozogamicin (GO)                 (51)
SGN-CD33A                       Seattle Genetics
                                (12,13)
                                Sanofi
AVE9633                         (53)
Targeting CD19 antigen, a TPI on B cells as an accessory molecule for
B-cell signal transduction and TAA:
SAR34I9,                        ImmunoGen
coltuximab
ravtansine                      (7,34,35)
SGN-CD19A                       Seattle Genetics
                                (32)
ADCT-402                        ADC Therapeutics S.A.
                                (33)
Targeting Mesothelin antigen, a glycophosphatidyl inositol anchored
protein:
BAY 94-9343,                    Bayer
anetumab ravtansine             (57)
BMS-986148                      Bristol-Myers
                                (58)
DMOT4039A                       Genentech, Inc.
                                (59,60)
Targeting CD22 antigen, a transmembrane sialoglycoprotein functions as
an inhibitory receptor for BCR signaling and BCR -induced cell death:
Inotuzumab, IO,
Ozogamicin, CMC-                Pfizer
544                             (12)
Pinatuzumab
vedotin,                        Genentech, Inc.
DCDT2980S,                      (61)
RG7593
Targeting CEACAM5 antigen, labetuzumab, CEA, CD66e, a EGP that has a
role in cell adhesion and invasion:
IMMU-130,
hMN14-SN38,
labetuzumab                     Immunomedics
govitecan,                      (63-65)
labetuzumab-SN-38
SAR40870                        Sanofi
                                (66)
Targeting Trop-2 (MIS), TACSTD2 or GA733-1) antigen, a EGP transduces
calcium signal has a role in ERK1/2 MAPK pathway which mediates cancer
cell proliferation, migration, invasion, and survival:
IMMU-132, hrS7-SN-38,
Sacituzumab                     Immunomedics
govitecan                       (67-72)
PF-06664178, Trop-              Pfizer
2 ADC, RN927C                   (73)
Targeting PSMA antigen, a TP2 has known enzymatic activities and acts
as a glutamate-preferring carboxypeptidase:
PSMA ADC                        Progenics
                                (74,75)
MLN2704                         Millennium
                                (76)
Targeting CD37 (Tetra spanin-26) antigen, a TP3 present on mature B
cells, implicates as a signaling death receptor to regulate B/T-cell
interactions /proliferation:
1MGN529,
Naratuximab                     ImmunoGen
emtansine                       (78,79)
AGS67E                          Agensys
                                (80-81)
Targeting CD30 (TNFRSF8) antigen, a tumor necrosis factor:
Adcetris,                       Seattle Genetics
brentuximab
vedotin, SGN-35                 (6,7)
Targeting HER3 antigen, a member of EGFR family RTK, frequently
overexpressed in solid tumors, including breast, lung, and colorectal
tumors of epithelial origin; it has no active kinase domain itself but
is activated through heterodimerization with other members of the EGFR
family:
                                Daiichi Sankyo,
U3-1402                         Inc.
                                (82)
Targeting DLL3 antigen, scr-like kinase (Fyn3) acts as a notch ligand
for cell-cell communication:
Rovalpituzumab                  Stemcentrx
tesirine, Rova-T,               (83)
SC16LD6.5
Targeting GPNMB antigen, an EGP is involved in differentiation of
osteoblasts, and cellular adhesion:
Glembatumumab                   Celldex Therapeutics
Vedotin (GV),                  (84-87)
CDX-011,CR011-vcMMAE
Targeting CD79b antigen, a TP1 on B cells mediates signal transduction
cascade activated by BCR:
Polatuzumab                     Genentech, Inc.
vedotin, RG7596,
DCDS4501A                       (88)
Targeting GCC antigen, a part of calcium negative fccdback system and
has a role in cGMP synthesizes from GTP:
Indusatumab
vedotin,                        Millennium
MLN0264,TAK-                    (89,90)
264, 5F9-VCMMAE
Targeting NaPi2b antigen, a sodium phosphate transporter:
Lifastuzumab
vedotin, RG7599,                Genentech, Inc.
DN1B0600A                       (91,92)
Targeting CA6 antigen, a sialoglycotopeof MUC-1 is over-expressed in
variety of solid tumors, including breast, ovarian, cervical, lung and
pancreatic tumors:
SAR566658                       Sanofi
                                (93,94)
Targeting CD74 antigen, a TP2 on B cells involved in the formation and
transport of MHC class II protein:
Milatuzumab-doxorubicin,        Immunomedics
IMMU-110, hLLl-                 (95)
DOX
Targeting CD138 antigen, syndecanl, a type I transmembrane heparan
sulfate proteoglycan participates in cell proliferation, cell migration
and cell -matrix interactions:
BT-062,
Indatuximab                     Biotest
ravtansine                      (96)
Targeting BCMA antigen, a receptor for a proliferation-inducing ligand
and B-cell activating factor:
GSK2857916                      GlaxoSmithKine
                                (97)
Targeting specific myeloma antigen:
DFRF4539A,                      Genentech, Inc.
RG7598                          (100)
Targeting SLAMF7(CSI) antigen:
                                Abbvie
ABBV-838
                                (101)
Targeting CD56 antigen, associates with FGFR and stimulates RTKs to
induce neurite outgrowth:
IMGN901,
Lorvotuzumab                    ImmunoGen
mertansine,                     (102)
huN901-DM1/BB-10901
Targeting ENPP3 (CD203c) antigen, a TP2 belongs to a series of
ectoenzymes, possess ATPase and ATP pyrophosphatase activities:
                                Astellas Pharma
AGS-16C3F
                                (103,104)
Targeting TF(CD142) antigen, a TP and initiator of the coagulation
cascade:
Humax-TF-ADC,                   Genmab
tisotumab vedotin               (105)
Targeting TIM1 antigen, a member of the T cell transmembrane IgG and
mucin family, which plays critical roles in regulating immune cell
activity especially regarding the host response to viral infection:
                                Celldex
CDX-014                         Therapeutics
                                (106)
Targeting FOLR1 antigen, a membrane-bound protein regulates transport
of the vitamin B9 into cells:
IMGN853,                        ImmunoGen
mirvetuximab                    (17,107-110)
soravtansine
Targeting MUCI6 (CA-125) antigen, a member of the mucin family GP that
acts as a lubricating barrier against foreign particles and infectious
agents on the apical membrane of epithelial cells:
RG7458,
Sofituzumab                     Genentech, Inc.
Vedotin,                        (HI)
DMUC5754A
Targeting CanAg antigen, is a novel glycoform of mucin family GP:
IMGN242, HuC242-                ImmunoGen
DM4, cantuzumab                 (112)
ravtansine
Targeting Ckit(CD117 or SCFR) antigen, a TP and RTKs having a key role
in the regulation of cell differentiation and proliferation:
LOP628, Anti c-KIT              Novartis
ADC                             (113)
Targeting EphA2 antigen, belonging to ephrin receptor subfamily of the
RTKs family regulating cell migration, adhesion, proliferation and
differentiation:
MEDI-S47, MI-                   Medimmune
CP177                           (114,115)
Targeting Nectin 4 (PVRL4) antigen, a TP1 and member of a family of
cellular adhesion molecules, involved in Ca2+- independent cellular
adhesion:
ASG-22ME, AGS-22M6E,
anti-nectin-                     Astellas Pharma
4 ADC, Enfortumab               (116,117)
vedotin
Targeting SLTRK6 antigen, belonging to the integral TPs(SLITRK) with
LRR:
AGS15E,anti-                    Agensys
SLITRK6 ADC                     (119)
Targeting HGFR (cMet) antigen, RTKs for hepatocyte growth factor:
ABBV-399,
Telisotuzumab                   Abbvie
vedotin                         (120-123)
Targeting FGFR2 antigen, type 2 RTKs with a role in both embryonic
development and tissue repair:
BAY1187982, anti-               Bayer
FGFR2 ADC,                      (124)
Aprutumab ixadotin
Targeting C4.4a (LYPD3) and uPAR antigen, glycosylphosphatidylinositol
(GPI)-anchored proteins:
BAYI 129980,
Lupartumab                      Bayer
amadotin, anti-                 (125)
C4.4a ADC
Targeting p-Cadherin (Cadherin 3) antigen, a cell-surface protein and
member of the cadherin family plays a role in cell adhesion, motility,
invasion, and proliferation:
PCA062                          Novartis
                                (126)
Targeting 5T4 (TPBG) antigen, a EGP correlated with increased
invasiveness:
PF-06263507, anti-              Pfizer
5T4 ADC                         (127)
Targeting STEAPI antigen, cell-surface protein is predominantly
expressed in prostate tissue:
RG7450,
DSTP3086S,
Vandortuzumab                   Genentech, Inc.
vedotin, STEAPI                 (128-131)
ADC
Targeting PTK7 antigen, RTKs 7 presents on TICs in the Wnt signaling
pathway:
PF-06647020,
h6M24-vc0101,                   Pfizer
PTK7-targeted                   (132,133)
ADC
Targeting Ephrin-A4 (EFNA4) antigen, RTKs modulate signaling pathways
that impact cell fate decisions during embryogenesis and adult tissue
homeostasis:
                                Pfizer
PF-06647263                     (113,134)
Targeting LIV1(SLC39A6 or ZIP6) antigen, a member of the zinc
transporter family playing a key role in tumor cell progression and
metastasis:
SGN-LIVIA,                      Seattle Genetics
anti-LIV-1                      (135)
Targeting TENB2 antigen, a prostate cancer target associated with the
progression of poorly differentiated and androgen-independent tumor
types:
Anti-TENB2 ADC                  Seattle Genetics
                                (131,139)
Targeting ETBR antigen, a G-protein coupled receptor that can activate
RAF/MEK signaling:
RG7636,                         Genentech, Inc.
DEDN-6526A                      (140)
Targeting integrin v3 antigen:
IMGN-388                        ImmunoGen
                                (141)
Targeting crypto antigen, belonging to the EGF-CFC family of growth
factor-like molecules, playing a key role in signaling pathways of
certain transforming growth factor-beta super- family members:
BIIB-015                        Biogen
                                (142)
Targeting AGS-5 (SLC44A4) antigen, a sodium -dependent transmembrane
transport protein:
ASG-5ME                         Seattle Genetics/Astellas
                                (143)
Targeting LY6E antigen, an interferon (IFN)- inducible
glycosylphosphatidyl inositol (GPI)-linked cell membrane protein:
RG7841,                         Genentech, inc.
DLYE5953A                       (144)
Targeting AXL (UFO) antigen, a member of the TAM (TYRO3, AXL and MER)
family of RTK, playing a key role in tumor cell proliferation,
survival, invasion and metastasis:
HuMax-Axl-ADC                   Genmab
                                (145)
Targeting CD205 antigen, a type I C-type lectin receptor normally
expressed on various APC and some leukocyte sub-populations:
                                Menarini
MEN1309/OBT076                  Ricerche
                                (146)
Targeting CD25 (IL-2 Ralpha) antigen, a TP and tumor-associated antigen
(TAA), expressed on certain cancer cells:
ADCT-301,anti-                  ADC Therapeu-ticsS.A.
CD25-PBD ADC                    (147)
Targeting LAMP-1 antigen, playing a key role in cell-cell adhesion and
migration:
SAR428926                       Sanofi
                                (148)
Targeting MN/CA IX antigen, a TGP expressed in some human carcinomas
and appears to be involved in cancer cell proliferation and
transformation:
ADC BAY79-4620,                 Bayer
MN-IC                           (149)

Not available (n/a). Relapsed B-cell non-Hodgkin's lymphoma (B-NHL),
Acute myeloid leukemia (AML), Mertansine (DMI), Calicheamicin (calich.)
, N-succinimidyl 4-(N-maleimidometliyl) cyclohexane-lcarboxylate
(SMCC), Hydrazone acetyl butyrate (AcBut), Uterine Serous Carcinoma
(USC), Tumor-Associated Antigen (TAA), Valine-citrulline-seco (vc
-seco), Renal Cell Carcinoma (RCC), clear cell Renal Cell Carcinoma
(ccRCC), Mantle-Cell Lymphoma Diffuse (MCLD), Non Small-Cell Lung
Cancer (NSCLC), Receptor tyrosine kinases (RTKs), Recurrent
Glioblastoma Multiforme (GBM), Transmembrane Protein (TP), CD27 ligand
(CD27L), Epidermal growth factor receptor variant III (EGFRvIII),
Glioblastoma multiforme (GBM), Epithelial Ovarian Cancer (EOC), Head
and Neck Squamous Cell Carcinomas (HNSCC), Auristatin F
-hydroxypropylamide (AF-HPA), Polyacetal-based polymer (Fleximer[R]),
Non-natural amino acid linker para-acetyl-phenylalanine (pAcF),
Amberstatin, a short polyethylene glycol (PEG) spacer terminated by an
alkoxyamine (AS269).
B Cell Receptor (BCR), Chronic Lymphocytic Leukemia (CLL),
Prostate-specific membrane antigen (PSMA), Maleimido -[short
PEG]-Lys-PABOCO-20-0 (CL2A), Metastatic colorectal cancer (mCRC),
Carcinoembryonic Antigen Related Cell Adhesion Molecule 5 (CEACAM5),
Trophoblast cell-surface antigen 2 (Trop-2), Tumor -Associated Calcium
Signal Transducer (TACSTD2), Gastric Antigen 733-1 (GA733-1), Malignant
Pleural Mesothelioma (MPM), Platinum-resistant ovarian cancer (P-OC).
Target sodium phosphate transporter 2b (NaPi2b), Transmembrane cell
surface receptor guanylyl cyclase C (GCC), Delta-like protein 3 (DLL3),
polyethylene glycol spacer (PEGS), Selective Catalytic Reduction (scr),
Metastatic Urothelial Cancer (MUC), B-Cell Maturation Antigen (BCMA),
DX-8951 a derivative of the camptothecin analog exatecan (DXd).
Folate receptor l(FOLRl), Maleimidocaproyl-valine-citrulline- (MC-VC
-PABC), Carbohydrate antigen 125 (CA-125), Mucin 16 (MUC16), A high
molecular weight mucin-type glycoprotein (CanAg), Erythropoietin
producing hepatoma A2 receptor (EphA2 or EPHA2), Ectonucleotide
pyrophosphatase/phosphodiesterase family member 3 (ENPP3), Poliovirus
receptor related protein 4 (PVRL4), 2 N-terminal Leucine-Rich Repeat
(LRR), Human Tissue Factor (TF), Stem Cell Factor Receptor c-Kit (SCFR).
Hepatocyte Growth Factor Receptor (HGFR), Structural homolog of the
urokinase-type Plasminogen Activator Receptor (uPAR), Tumor-associated
antigen (C4.4a), Lung Squamous Cell Carcinoma (LSCC), Fibroblast growth
factor receptor type 2 (FGFR2), Ovarian Cancers (OC), Trophoblast
Glycoprotein (TPBG), metastatic Castration-Resistant Prostate Cancer
(mCRPC), - transmembrane epithelial antigen of the prostate-1 (STEAPI),
Anti-solute carrier family 39 zinc transporter member 6 (SLC39A6;
LIV-1; ZIP6), Anti-Endothelin B Receptor (ETBR), Auristatin-0101
(Aur0101).
Lymphocyte antigen 6 complex locus E (Ly6E), Antigen-Presenting Cell
(APC), a Slibunit of the iilterleukin-2 receptor (IL-2R alpha),
Lysosome-Associated Membrane Protein 1 (LAMP1).
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Author:Nejadmoghaddam, Mohammad-Reza; Minai-Tehrani, Arash; Ghahremanzadeh, Ramin; Mahmoudi, Morteza; Dinar
Publication:Avicenna Journal of Medical Biotechnology (AJMB)
Article Type:Report
Date:Jan 1, 2019
Words:20350
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