Table 1.
Antibody‐drug conjugates for breast cancer
| Drug name | Status | Antibody, target | Cytotoxic drug, target | Target patients | Potency/Efficacy |
|---|---|---|---|---|---|
| Kadcyla® | Approved | Trastuzumab, HER2 | Emtansine, antimicrotubule | HER2‐positive metastatic breast cancer | Improved overall survival compared to lapatinib plus capecitabine.112 |
| Glembatumumab vedotin | Phase 2b | Glembatumumab, Glycoprotein NMB | Monomethyl auristatin E (MMAE), tubulin inhibitor | gpNMB overexpressing metastatic triple‐negative breast cancer | Well‐tolerated in pretreated patients.122 |
| BMS‐182248‐1 (discontinued) | Phase 2 | BR96, Lewis‐Y antigen | Doxorubicin, topoisomerase II inhibitor | Metastatic breast cancer | Limited clinical activity.110 |
| IMMU‐132 | Phase I | Sacituzumab govitecan, antitrop‐2 | SN‐38, topoisomerase I inhibitor | Metastatic triple‐negative breast cancer | Well‐tolerated and robust response.6 |
| BAY 1187982 | Phase I | FGFR2, FGFR2 receptor | Auristatin, antimicrotubule | Cancer cells overexpressing FGFR | Effective compared to unconjugated antibodies in vitro102 |
| SYD985 | Phase I | Trastuzumab, HER2 receptor | Seco‐duocarmycin, DNA‐alkylating agent | BT‐474 cells and BT‐474 xenografted mice | Effective in BT‐474 xenografted in vivo model.33 |
| Anti‐PTK7‐Aur0101 | In vivo | Anti‐PTK7, antiprotein tyrosine kinase 7 antibody | Aur0101, microtubule inhibitor | Triple‐negative breast cancer | Induced sustained tumor regression.17 |
| REGN2878‐DM1 | In vivo | REGN2878, prolactin receptor | DM1, maytansine derivative | Prolactin receptor‐positive breast cancer | Significant antigen‐specific antitumor activity.57 |
| DS‐8201a | In vivo | Trastuzumab, HER2 receptor | Exatecan derivatives, topoisomerase I inhibitor | Both HER2 + and HER2‐ breast cancer cells | Showed bystander toxicity.83 |
| BT‐2111 | In vivo | Trastuzumab, HER2 receptor | Melanotransferrin, cross blood‐brain barrier | Breast cancer metastasis to the brain in NuNu mice | 68% reduction of metastasis in the brain compared to trastuzumab alone.82 |
| FGF1V‐MMAE | In vitro | FGF1 receptor ligand variant (FGF1v), FGFR | MMAE, tubulin inhibitor | Cancer cells overexpressing FGFR | Conjugate showed higher potency than MMAE.106 |
Antibody‐cytotoxic drug conjugates (ADCs) are the most widely investigated drug conjugates to treat breast cancer.89 In general, a cytotoxic drug is attached to a monoclonal antibody that is specific for the target receptor (Figure 2A). The antibody binds to the receptor of the cancer cell where the cytotoxic drug is intended to exert its actions. Therefore, the cancer cells should ideally densely express the receptor for antibody binding. Although over 55 ADCs are currently in clinical trials,13 only 3 ADCs have been approved by the FDA.77 However, gemtuzumab ozogamicin (marketed as Mylotarg® by Wyeth‐Ayerst) was withdrawn in 2010 due to increased patient mortality and demonstrating no clinical benefit over conventional therapy, which leaves only 2 ADCs available for clinical use. One of them is for HER2‐positive metastatic breast cancer—the trastuzumab‐emtansine conjugate marketed as Kadcyla® by Genentech and Roche. Another one is brentuximab‐vedotin (Adcetris® marketed by Seattle Genetics) for Hodgkin lymphoma or anaplastic large cell lymphoma. In many ways, ADCs may exert potential benefits over conventional treatment. For example, highly cytotoxic drugs might become safer for normal cells when they are bound to cancer cell‐specific antibodies.115