Breast cancer is the leading cause of death among women worldwide. When breast cancer spreads to other parts of the body, the prognosis is poor. Currently, there is no treatment for metastatic breast cancer. Antibody-drug conjugates (ADCs) are new anti-cancer drugs composed of antibodies, ADC linkers and cytotoxic agents. The monoclonal antibodies in the ADC target specific antigens, and the cytotoxic agent kills cancer cells without harming surrounding healthy cells. Ado-trastuzumab Emtansine (T-DM1), Fam-trastuzumab Deruxtecan (T-DXd) and Sacituzumab govitecan (SG) are FDA-approved ADCs for the treatment of breast cancer. T-DM1 and T-DXd target human epidermal growth factor receptor 2 (HER2), while SG targets trophoblast surface antigen 2 (TROP-2). Datopotamab deruxtecan (Dato-DXd) is an investigational ADC targeting TROP2. In the TROPION-Breast01 Phase III trial, the drug showed a clinically meaningful improvement in progression-free survival in breast cancer patients. Both TROP-2 and HER2 are involved in cancer cell proliferation. In addition to HER2 and TROP2, there are other proteins involved in tumor progression that could serve as important targets for ADCs.
Nectin Cell Adhesion Molecule 4 (Nectin-4)
Nectin-4 is a cell surface protein that plays an important role in cell-cell adhesion. It is overexpressed in breast cancer and other malignancies and promotes cancer cell proliferation and metastasis. Enfortumab vedotin (EV), a nectin-4-targeting ADC, has been approved by the FDA for the treatment of urothelial cancer. The drug has also been approved in the EU and China. The EV-202 Phase 2 trial is ongoing to test the efficacy of EVs in breast cancer and other nectin-4-expressing cancers.
Tissue Factor (TF)
TF is a transmembrane protein mainly involved in blood coagulation. Scientists have discovered that this protein can promote cancer progression and metastasis. Tisotumab vedotin (TV), a TF-targeting ADC, has received accelerated approval from the FDA for the treatment of cervical cancer. However, this ADC has not yet been tested in breast cancer patients. XB002 is another ADC targeting TF. Scientists found in preclinical studies that the drug was effective against different types of tumors. XB002 caused reversible adverse reactions such as dry eye and non-infectious conjunctivitis in patients with solid tumors in phase I clinical trials.
Mesothelin
Mesothelin is another cell surface protein that plays an important role in cell adhesion. This cell surface protein is mainly expressed in mesothelial cells of the conjunctiva, pericardium, and cornea. It is also overexpressed in cancer and associated with poor prognosis. Anetumab ravtansine (AR) and RC88 are two ADCs that target mesothelin. In Phase I clinical trials, anetumab ravtansine caused manageable adverse effects, such as keratitis, fatigue, and anorexia, in patients with solid tumors. Both ADCs are being tested in phase 1/2 trials in triple-negative breast cancer and other solid tumors.
LIV-1
LIV-1 is a transmembrane protein that transports zinc into cells and is overexpressed in breast tumors. LIV-1 expression is associated with cancer metastasis and lymph node involvement. Ladiratuzumab vedotin (LV or SGN-LIV1A) is an ADC consisting of a monoclonal antibody targeting LIV1. This ADC can induce immunogenic cell death, which may be beneficial for patients undergoing immunotherapy. The drug’s efficacy is being tested in a Phase 1 clinical trial in patients with LIV1-positive breast cancer. Preliminary results from the clinical trial showed an overall response rate (ORR) of 32% in breast cancer patients. Median progression-free survival (PFS) was 11.3 weeks. This drug can cause nausea, hair loss, fatigue, and peripheral neuropathy in patients. Preliminary results from a phase Ib/II trial showed an ORR of 35% in triple-negative breast cancer patients treated with the combination of ladiratuzumab vedotin and pembrolizumab.
Receptor Tyrosine Kinase-Like Orphan Receptors 1 and 2
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) plays an important role in nervous system development. It is overexpressed in triple-negative breast cancer and has shown antitumor activity against this breast cancer subtype in xenograft models. NBE-002 is an anti-ROR1 ADC being tested in patients with solid tumors in a Phase 1/2 clinical trial. Receptor tyrosine kinase-like orphan receptor 2 (ROR2) plays an important role in the development of the skeletal system. It also promotes breast cancer metastasis, leading to poor prognosis. Ozuriftamab vedotin (BA3021) is a conditionally active biological (CAB) ADC targeting ROR2 that is being tested in a Phase 1/2 clinical trial.
Human Epidermal Growth Factor Receptor 3 (HER3)
HER3 belongs to the human epidermal growth factor receptor (HER) family. The tyrosine kinase activity of HER3 is weak and cannot transduce signals. Therefore, it forms heterodimeric complexes with hepatocyte growth factor receptor (HGFR), fibroblast growth factor receptor 2 (FGFR2), and other receptor tyrosine kinases (RTKs). It is overexpressed in breast cancer and other cancers such as melanoma and head and neck cancer. Patritumab deruxtecan is an ADC targeting HER3 that has been tested in breast cancer patients in a Phase 1/2 clinical trial. The ORR for patients with HR-positive/HER3 high & low/HER2-negative breast cancer who received this drug was 30.1%. The drug also causes adverse effects such as decreased platelet and neutrophil counts and anemia.
Globohexaosylceramide (Globo-H)
Globo-H is a carbohydrate antigen expressed in cancer cells. OBI-999 is an anti-Globo-H ADC that has been tested in patients with solid tumors in a Phase 1 clinical trial. Patients received the drug intravenously at varying doses and found the drug to be well tolerated at doses up to 1.2 mg/kg. The drug causes adverse reactions such as anemia and neutropenia.
Folate Receptor Alpha (FRα)
FRα is a membrane-bound protein involved in folate transport. It is expressed in triple-negative breast cancer. MORAb-202 is an ADC consisting of a monoclonal antibody targeting FRα. In xenograft mouse models, the drug inhibited proliferation of FRα-expressing cell lines. In a phase 1 clinical trial in which the drug was administered to patients with solid tumors, common adverse reactions observed in patients were neutropenia and leukopenia.
B7 Homolog 4 Protein (B7-H4)
B7-H4 is an immune checkpoint protein that inhibits the function of activated T cells. It is expressed in breast cancer and other tumors such as endometrial and cholangiocarcinomas. AZD8205 and SGN-B7H4V are two novel ADCs targeting FRα. Both ADCs showed antitumor activity in mouse models. A Phase 1/2 clinical trial is underway to evaluate the safety of AZD8205 in tumors such as breast cancer. SGN-B7H4V is also currently being tested in Phase 1 clinical trials in breast cancer and other tumors.
ADCs have been developed against these targets, and many of them have been found to be well tolerated in clinical trials. Scientists hope that some of these ADCs may be effective in treating metastatic breast cancer.
References
- Kundu, C.N. et al. Nectin cell adhesion molecule-4 (NECTIN-4): A potential target for cancer therapy. European Journal of Pharmacology. 2021, 911: 174516.
- Agostinelli, V. et al. Therapeutic Potential of Tisotumab Vedotin in the Treatment of Recurrent or Metastatic Cervical Cancer: A Short Report on the Emerging Data. Cancer Management and Research. 2023, 1063-1072.
- Rizzo, A. et al. Ladiratuzumab vedotin for metastatic triple negative cancer: preliminary results, key challenges, and clinical potential. Expert opinion on investigational drugs. 2022, 31(6): 495-498.
- Zhao, Y. et al. Tyrosine kinase ROR1 as a target for anti-cancer therapies. Frontiers in Oncology. 2021, 11: 680834.
- Yonesaka, K. et al. HER2-/HER3-Targeting Antibody-Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors. Cancers. 2021, 13(5): 1047.