Breast cancer is a common type of cancer, and its treatment methods include surgery, radiation therapy, chemotherapy, and targeted therapy. In recent years, antiboday-drug conjugate (ADC) drugs have been widely used in the treatment of breast cancer, including Ado-trastuzumab Emtansine (T-DM1), Fam-trastuzumab Deruxtecan (T-DXd), and Sacituzumab govitecan (SG). These drugs primarily target HER2 and TROP-2 and have been widely used in clinical practice with good efficacy.

However, besides HER2 and TROP-2, there are also some new antigen targets actively being researched, including Nectin-4, HER3, tissue factor (TF), FRα, LIV-1, ROR1-2, and B7-H4, etc. Research on these targets has shown promising initial results, bringing new hope for breast cancer treatment.

Nectin-4

The nectin cell adhesion protein 4 (Nectin-4) is a junction protein involved in the formation and maintenance of cell junctions. Nectin-4 was found to be overexpressed and served as an inducer in various malignant tumors, including BC, OC, colorectal cancer (CRC), PC and lung cancer.

Figure 1. Structure of Nectin-4, source: refrence [3]

Enfortomab vedotin is the first ADC targeting Nectin-4 to be studied, which is conjugated to MMAE via a cleavable linker. Initially, based on efficacy data from the phase 2 clinical trial EV-201, Enfortomab vedotin received accelerated approval from the FDA in 2019 for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) patients. Subsequently, FDA granted regular approval based on the positive results from the phase 3 clinical trial EV-301. Currently, the phase 2 trial EV-202 is underway to assess the efficacy of Enfortomab vedotin in breast cancer and other cancers expressing Nectin-4.

LIV-1

LIV-1 is a transmembrane protein that transports zinc into cells and is overexpressed in breast tumors. Its expression is associated with cancer metastasis and lymph node involvement.

Ladiratuzumab vedotin (LV or SGN-LIV1A) is an ADC composed of a monoclonal antibody targeting LIV1. This ADC can induce immunogenic cell death, which is beneficial for patients receiving immunotherapy. Ladiratuzumab vedotin is currently undergoing phase 1 clinical trials for LIV-1 positive metastatic HR-positive/HER2-negative and TNBC patients (NCT01969643). Preliminary results from this clinical trial show an overall response rate (ORR) of 32% in breast cancer patients. The median progression-free survival (PFS) is 11.3 weeks. This drug may cause patients to experience nausea, hair loss, fatigue, and peripheral neuropathy. Preliminary results from the phase Ib/II trial (SGNLVA-002) show an ORR of 35% in triple-negative breast cancer patients treated with ladiratuzumab vedotin and pembrolizumab combination therapy, including 2 complete responses, 21 partial responses, and stability in 32 patients' conditions.

Figure 2. Structure of ladiratuzumab vedotin, source: reference [9]

Tissue Factor (TF)

Tissue factor (TF) is an integral membrane protein, normally separated from the blood by the vascular endothelium, which plays a key role in the initiation of blood coagulation. Scientists have found that this protein can promote cancer progression and metastasis. TF protein is expressed in various tissues and tumors, including ovarian cancer, prostate cancer, bladder cancer, esophageal cancer, breast cancer, endometrial cancer, and lung cancer.

Tisotumab vedotin (TV) is an ADC targeting TF that has received FDA accelerated approval for the treatment of cervical cancer. However, this ADC has not been tested in breast cancer patients.

Figure 3. Mechanism of action of Tisotumab vedotin, source: reference [20]

XB002 is another ADC targeting TF. Scientists have found in preclinical studies that this drug is effective against different types of tumors. XB002 caused reversible adverse reactions such as dry eye and non-infectious conjunctivitis in phase I clinical trials in solid tumor patients.

Mesothelin

Mesothelin is a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein. Mesothelin expression in normal human tissues is limited to mesothelial cells lining the pleura, pericardium and peritoneum. However, mesothelin is highly expressed in several human cancers, including virtually all mesotheliomas and pancreatic adenocarcinomas, and approximately 70% of ovarian cancers and 50% of lung adenocarcinomas.

Though current development of mesothelin ADC primarily focuses on ovarian cancer, mesothelioma, non-small cell lung cancer, pancreatic cancer, and gastric cancer, ongoing trials also include breast cancer. Currently, two phase 1/2 trials are investigating the activity of ADCs targeting mesothelin, such as anetumab ravtansine and RC88, in solid tumors, including advanced TNBC.

HER3

HER3 belongs to the human epidermal growth factor receptor (HER) family. HER3 cannot activate signaling within homodimers due to its lack of kinase activity. Therefore, it forms heterodimer 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.

Figure 4. Mechanism of action of HER2 and HER3 directed ADC, source: reference [19]

Patritumab deruxtecan is a novel HER3 ADC composed of humanized monoclonal antibody patritumab and deruxtecan, with a DAR of 8. Phase 1/2 studies have been conducted in HER3-positive metastatic breast cancer patients (NCT02980341). The overall response rate (ORR) for HR-positive/HER3-high & low/HER2-negative breast cancer patients receiving this drug was 30.1%. No patients exhibited complete remission. The drug also caused adverse reactions such as decreased platelet and neutrophil counts, as well as anemia.

ROR1 & ROR2

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) plays important roles in organogenesis, tissue regeneration, nervous system development and has been recently reported to aberrantly express in various types of cancers but not a variety of normal adult tissues. It is overexpressed in triple-negative breast cancer and has shown anti-tumor activity against this breast cancer subtype in xenograft models. NBE-002 is an anti-ROR1 ADC currently being tested in phase 1/2 clinical trials in patients with solid tumors.

Figure 5. Structure of ROR1, source: reference [18]

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) plays an important role in skeletal system development. It also promotes breast cancer metastasis, leading to poor prognosis. Ozuriftamab vedotin (BA3021) is a conditional activity-based (CAB) ADC targeting ROR2. It is also being tested in phase 1/2 clinical trials.

Globohexaosylceramide (Globo-H)

Globo H a tumor-associated carbohydrate antigen that is overexpressed on a variety of epithelial cell tumors such as colon, ovarian, gastric, pancreatic, lung, prostate, and breast cancers.

In breast cancer, Globo-H has been extensively researched and utilized in the development of therapeutic cancer vaccines with promising results. The ADC drug OBI-999 is composed of a humanized monoclonal antibody targeting Globo-H, linked to MMAE via a cleavable linker, and is currently in early clinical stages. In late-stage solid tumor patients, intravenous administration of the drug at different doses showed good tolerance, particularly at doses as high as 1.2 mg/kg. Adverse reactions observed with this drug include anemia and neutropenia.

Folate Receptor α(FRα)

FRα is a membrane-bound protein involved in folate transport. It is expressed in triple-negative breast cancer. MORAb-202 is an ADC composed of a monoclonal antibody targeting FRα. In xenograft mouse models, this drug inhibited the proliferation of cell lines expressing FRα. In a phase 1 clinical trial, the drug was administered to patients with solid tumors, and common adverse reactions observed in patients included neutropenia and leukopenia.

B7H4

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 cholangiocarcinoma. AZD8205 and SGN-B7H4V are two novel ADCs targeting FRα. Both ADCs have shown 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, and SGN-B7H4V is currently being tested in a phase 1 clinical trial in breast cancer and other tumors.

References:
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