Antibody-drug conjugates (ADCs) combine the advantages of high targeting of antibody drugs and high activity of Payload in tumor tissues, providing better efficacy than traditional antibody-based therapeutic agents and demonstrating great clinical value.

ADC has become another popular field after the immune checkpoint inhibitors represented by PD-1/PD-L1, and companies need to speed up the R&D progress in order to seize the first-mover advantage. Reasonable selection of targets is crucial if companies want to survive or even stand out.

Approved ADCs

Currently, there are over 100 ADC drugs in various stages of development worldwide, of which 15 have been approved for marketing, a dozen have entered clinical phase III, and most are still in clinical phase I and preclinical stages.

Among the 15 approved ADC drugs, 7 are for the treatment of hematological tumors and 8 are for the treatment of solid tumors. There are 11 targets involved, namely CD33, CD30, HER2, TROP2, BCMA, EGFR, CD19, CD22, CD79b, Nectin-4 and TF, with three targeting HER2 and two targeting CD22. The overall global market for ADC drugs has exceeded US$5 billion in 2021.

Table 1. FDA Approved ADC Drugs, source: reference 1

Of the the ADC drugs under investigation, the more popular targets include HER2, EGFR, CLDN18.2, TROP2, c-Met, CD19, PSMA, Muc1, BCMA and PDL1, most of which are validated mature targets.

Figure 1. The important target antigens from tumor cells (overexpressed and driver genes) and tumor microenvironment (vasculature and stroma) are used for the development of ADC. Source: reference 1

ADCs in Clinical Trails

HER2-Directed ADCs

HER2, known as human epidermal growth factor receptor 2, is a receptor tyrosine kinase on the surface of cell membranes that regulates cell proliferation and differentiation. Currently, abnormal expression of HER2 is found in breast cancer, ovarian cancer, gastrointestinal cancer, lung cancer and non-small cell carcinoma.Tumors with high HER2 expression exhibit strong metastatic and infiltrative ability, poor sensitivity to chemotherapy, and are prone to recurrence.

Several HER2 ADC products are currently available, including Kadcyla, Enhertu and Disitamab vedotin. And a number of next-generation HER2-targeted ADCs are currently under investigation in clinical trials.

Table 2. Pharmacological properties of anti-HER2 ADCs undergoing clinical trials

EGFR-Directed ADCs

Epidermal growth factor receptor  (EGFR), also known as HER1/ErbB1,  is an important signaling molecule for normal cell proliferation in humans, and its overexpression can lead to tumorigenesis. A variety of solid tumor tissues of epithelial origin, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, kidney cancer, and bladder cancer, have high EGFR expression and this group of patients has a poor prognosis.

The only EGFR ADC drug currently available is Cetuximab sarotalocan (also known as RM-1929) which was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. It is a novel ADC consisting of an anti-EGFR chimeric monoclonal antibody, cetuximab, conjugated with IRDye®700DX, a near-infrared photosensitizing dye. Three ADCs targeting EGFR are under clinical investigations, including depatuxizumab mafodotin (ABT-414), MRG003 and M1231. ABT-414 has been so far the most advanced investigational EGFR-driven ADC that has reached phase III trials.

Table 3. Summary of anti-EGFR ADCs in clinical investigation.

Trop-2-Directed ADCs

Trophoblast cell surface antigen 2 (TROP-2) promotes tumor cell growth, proliferation and metastasis mainly by regulating calcium signaling pathway, cell cycle protein expression and reducing fibronectin adhesion. TROP-2 is highly expressed in a variety of tumors, such as pancreatic, breast, colon, bladder, oral squamous and ovarian cancers, and its high expression is closely associated with shortened survival and poor prognosis of tumor patients.

Currently, Sacituzumab govitecan (Trodelvy) developed by Gilead Science is the only available TROP 2 inhibitor in the market which is indicated for the management of triple negative breast cancer and urothelial cancer.

Another important investigational drug, DS-1062 (datopotamab-deruxtecan), has shown good efficacy in multiline therapy-resistant non-small cell lung cancer, with at least 40% of patients experiencing 30% or more tumor shrinkage and nearly 80% of patients having good tumor control.

Figure 2. TROP-2 ADC ongoing trails

Tissue-factor Directed ADCs

Tissue factor (TF) is encoded by the F3 gene. It belongs to the cytokine receptor protein superfamily and is expressed in subendothelial tissue and leukocytes. During an abnormal expression, it is highly expressed in many solid cancers, including pancreatic, lung, cervical, prostate, bladder, ovarian, breast, and colon cancer.

The binding between factor VII (FVII) and TF generates an active TF:FVIIa complex responsible for activating the coagulation extravasation cascade. Physiologically, this pathway is induced by vascular injury, which leads to the exposure of normally hidden TF-positive cells to the blood. In contrast, TF is frequently expressed by tumor cells, including pancreatic, lung, cervical, prostate, bladder, ovarian, breast, and colon cancer, and has been shown to promote tumor growth, angiogenesis, metastasis, and thrombosis. Because of the limited selective expression of TF on normal cells and increased expression on malignant cells, it is currently being explored as a potential target for mAbs, small TKIs and ADCs.

Tivdak (Tisotumab vedotin), developed jointly by Seagen and GenMab, is the world's first TF ADC drug for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Figure 3. Tisotumab vedotin mechanism of action, source: Seagen official website

FRα-Directed ADCs

Folate Receptor alpha (FRα) belongs to FRs (composed of four isoforms α, β, γ and δ) and is the same cysteine-rich glycolipid-anchored protein as the FRβ isoform. FRα is encoded by the FOLR1 gene and is less expressed in normal tissues, but overexpressed in most solid tumors such as mesothelioma (72-100%), TNBC (35-68%), NSCLC (14-74%), ovarian cancer (76-89%), and endometrial cancer (20-50%).

Figure 4.  Cancers overexpressing folate receptor α (FRα) and concordant expression of FRα in non-malignant tissues, Adapted from Scaranti et al. 2020.28

Compared with the current hot targets such as HER2 and Trop2, the development of ADC drugs against the FRα target appears to be exceptionally cool, with only six companies worldwide currently laying out in this track. IMGN853 (MIRV, Mirvetuximab soravtansine), developed by ImmunoGen, has been approved by FDA in 2022. In addition, positive clinical results have been achieved with MORAb-202 as well as STRO-002.

c-Met-Directed ADCs

c-mesenchymal-epithelial transition factor (c-MET) is a receptor tyrosine kinase encoded by the proto-oncogene MET. It is currently the only known receptor with high affinity for its naturally occurring ligand, hepatocyte growth factor (HGF). The c-Met signaling pathway is frequently activated by cancer cells to promote tumor formation, aggressive growth and metastasis, and it is aberrantly expressed or mutated in many types of solid tumors such as lung, gastric, liver, breast, skin and colorectal cancers. At present, no c-Met ADCs have been approved, and most of them are in early stage of development.

AbbVie's Telisotuzumab vedotin progressed the fastest, with its phase II clinical results showing significant efficacy in treating patients with EGFR-negative non-small cell lung cancer (ORR: 35.1%, mDOR: 6.9m), with an ORR of 53.8% in patients with high c-Met expression and 25.0% in patients with low expression. However, the ORR among EGFR-positive patients was only 13.3%. In terms of safety, the incidence of grade 3 or higher treatment-related adverse events was 53.8%, and three patients reported possible treatment-related deaths.

Nectin-4-Directed ADCs

Nectin Cell Adhesion Molecule 4 (Nectin-4) is a type I membrane protein expressed mainly in the placenta and weakly to moderately expressed in normal human tissues such as skin, bladder, salivary glands, esophagus, breast and stomach. Nectin-4 is overexpressed in a variety of tumor cells, such as uroepithelial, breast, pancreatic, triple-negative breast and bladder cancers, and it activates the PI3K/Akt pathway to promote tumor cell proliferation and invasion.

Padcev is a first-in-class ADC drug that targets Nectin-4 by conjugating an anti-Nectin-4 monoclonal antibody with the microtubule-disrupting agent MMAE (monomethyl auristatin E).

Claudin18.2-Directed ADCs

The claudin18.2 (CLDN18.2) protein belongs to a family of Claudin integrin membrane proteins found in the tight junctions of the epithelium and endothelium. Claudin18.2 is normally buried in the gastric mucosa and cannot be bound by antibodies in normal tissues. In contrast, the development of malignant tumors leads to disruption of tight junctions, exposing the Claudin18.2 epitope on the surface of tumor cells as a specific target. Claudin18.2 is highly expressed in gastric cancer and is also expressed in pancreatic, esophageal and lung cancers.

Among the Cladin18.2-targeting ADC drugs currently in development, the one that is progressing faster is Zolbetuximab. Zolbetuximab has been shown to be highly selective for CLDN18.2 both in vivo and in vitro, binds to cancer-specific targets that are predominantly expressed in tumor cells and shows little or no binding in healthy tissues.

Huateng Pharma is dedicated to being your most reliable partner to provide chemical synthesis and high-quality PEG linkers for ADC drugs. We are committed to promoting the progress of your ADC discovery and development projects.

Two of the latest ADCs to be approved, Trodelvy and Zynlonta, were developed with PEG moiety as part of their linker technology to improve solubility and stability in vivo. 

Zynlonta, an FDA-approved drug targeting CD19, is used to treat relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), including patients treated with stem cell transplantation and CAR-T cell therapy.

PEG linker for Zynlonta

Trodelvy® (sacituzumabgovitecan-hziy) is used for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received at least two prior systemic therapies or at least one of them for metastatic disease. Sacituzumab-govitecan (IMMU- 132) is coupled to SN-38 via a cleavable maleimide linker with a short PEGylated unit.

PEG linker for Trodelvy

References:
1. Fu, Z., Li, S., Han, S. et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Sig Transduct Target Ther 7, 93 (2022). https://doi.org/10.1038/s41392-022-00947-7
2. Ferraro, E., Drago, J.Z. & Modi, S. Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions. Breast Cancer Res 23, 84 (2021). https://doi.org/10.1186/s13058-021-01459-y
3. Yu J, Fang T, Yun C, Liu X, Cai X. Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers. Front Mol Biosci. 2022 Feb 28;9:847835. doi: 10.3389/fmolb.2022.847835. PMID: 35295841; PMCID: PMC8919033.
4. Cao, W., Xing, H., Li, Y. et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res 10, 38 (2022). https://doi.org/10.1186/s40364-022-00385-1
5. Scaranti, M., Cojocaru, E., Banerjee, S. et al. Exploiting the folate receptor α in oncology. Nat Rev Clin Oncol 17, 349–359 (2020). https://doi.org/10.1038/s41571-020-0339-5

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