Many of the cytotoxic payloads linked to mAbs within ADCs are based on calicheamicin or microtubule-targeting agents (eg, maytansinoids, auristatin). Newer ADCs in development are attempting to find novel targets, including new DNA-damaging agents (topoisomerase inhibitors, DNA alkylating agents, DNA cross-linking agents), amanitins, immunomodulatory agents, and apoptosis inducers.

DNA-damaging payloads in clinical development include trastuzumab deruxtecan (topoisomerase I inhibitor) in HER2-positive metastatic breast cancer, NSCLC, and urothelial cancer. Sacituzumab govitecan also contains a topoisomerase I inhibitor, which also is the active metabolite of irinotecan and is being studied predominantly in epithelial cancers and was recently approved by the FDA for metastatic triple-negative breast cancer. Trastuzumab duocarmazine contains a novel DNA alkylating agent being studied in breast cancer.

HDP-101 is an anti-CD269 mAb linked to amanitin, which is typically too potent to administer systemically. Amanitins inhibit RNA polymerase 2, leading to reduced transcription. Clinical trials have not yet started, but preclinical data suggest possible effects in myeloma cell lines. 


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Moxetumomab pasudotox is approved for use in hairy cell leukemia, with its payload being an exotoxin derived from Pseudomonas. This toxin induces apoptosis by inhibiting elongation factor-2. These agents can potentially cause hemolytic uremic syndrome (HUS) and capillary leak syndrome, therefore, their safety profiles represent a potential concern. ABBV-155 targets B7-H3 and links to clezutoclax as its payload which inhibits Bcl-XL, inducing apoptosis. ABBV-155 is currently being studied in SCLC, NSCLC, and breast cancer.

Immunomodulatory ADCs use noncytotoxic payloads that activate myeloid antigen-presenting cells (APCs), which leads to stimulation of the immune system. SBT6050 contains a HER2 mAb linked to a toll-like receptor 8 (TLR8) agonist which can induce both macrophage killing of tumor cells and dendritic cells to promote tumor-specific cytotoxic T-lymphocyte responses. SBT6050 only has preclinical data to date, with clinical trials planned in the future. Additional agents being studied with similar payloads include BDC-1001 and NJH395; both of these investigational agents contain TLR7/8 payloads.

With all of these agents, it is important to note that many of the studies to date are early phase, and they can be associated with serious adverse events. Accumulating safety and efficacy data will be important to review as additional studies are completed.

Moving forward, it will be interesting to see how ADCs continue to develop from both from a safety and efficacy perspective. Developing the ideal ADC is multifactorial, with early studies yet to identify which component may be the most critical. Future studies will also evaluate how ADCs can be used with additional agents, especially within the immunotherapy class. Advanced and innovative basic and translational research will be critical to allow ADCs to progress through the drug development process.

References

  1. Boni V, Sharma MR, Patnaik A. The resurgence of antibody drug conjugates in cancer therapeutics: novel targets and payloads. Am Soc Clin Oncol Educ Book. 2020;40:1-17.
  2. Coats S, Williams M, Kebble B, et al. Antibody-drug conjugates: future directions in clinical and translational strategies to improve the therapeutic index. Clin Cancer Res. 2019;25:5441-5448.
  3. US Food and Drug Administration. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer [press release]. Published April 22, 2020. Accessed July 1, 2020.