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The target invites a foe: antibody-drug conjugates in gynecologic oncology
Maira P Campos1, Gottfried E Konecny
1Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Purpose Of Review:
Antibody-drug conjugates (ADCs) represent a promising new class of cancer therapeutics. Currently more than 60 ADCs are in clinical development, however, only very few trials focus on gynecologic malignancies. In this review, we summarize the most recent advances in ADC drug development with an emphasis on how this progress relates to patients diagnosed with gynecologic malignancies and breast cancer.
Recent Findings:
The cytotoxic payloads of the majority of the ADCs that are currently in clinical trials for gynecologic malignancies or breast cancer are auristatins (MMAE, MMAF), maytansinoids (DM1, DM4), calicheamicin, pyrrolobenzodiazepines and SN-38. Both cleavable and noncleavable linkers are currently being investigated in clinical trials. A number of novel target antigens are currently being validated in ongoing clinical trials including folate receptor alpha, mesothelin, CA-125, NaPi2b, NOTCH3, protein tyrosine kinase-like 7, ephrin-A4, TROP2, CEACAM5, and LAMP1. For most ADCs currently in clinical development, dose-limiting toxicities appear to be unrelated to the targeted antigen but more tightly associated with the payload. Rational drug design involving optimization of the antibody, the linker and the conjugation chemistry is aimed at improving the therapeutic index of new ADCs.
Summary:
Antibody-drug conjugates can increase the efficacy and decrease the toxicity of their payloads in comparison with traditional cyctotoxic agents. A better and quicker translation of recent scientific advances in the field of ADCs into rational clinical trials for patients diagnosed with ovarian, endometrial or cervical cancer could create real improvements in tumor response, survival and quality of life for our patients.
Insights
Antibody-drug conjugates (ADCs) offer improved cancer treatment efficacy and reduced toxicity. Advances in ADC development, particularly for gynecologic cancers, promise better patient outcomes and quality of life.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Antibody-drug conjugates (ADCs) are an emerging class of cancer therapeutics with significant potential.
- While numerous ADCs are in clinical development, few specifically target gynecologic malignancies.
Purpose of the Study:
- To review recent advancements in ADC drug development.
- To highlight the relevance of these advances for patients with gynecologic malignancies and breast cancer.
Main Methods:
- Review of current clinical trials and scientific literature on ADCs.
- Analysis of payloads, linkers, and target antigens in ADC development for gynecologic and breast cancers.
Main Results:
- Common payloads include auristatins, maytansinoids, calicheamicin, pyrrolobenzodiazepines, and SN-38, utilizing cleavable and non-cleavable linkers.
- Novel target antigens such as folate receptor alpha, mesothelin, and TROP2 are under investigation.
- Dose-limiting toxicities are primarily associated with payloads rather than targeted antigens, emphasizing the need for rational drug design.
Conclusions:
- ADCs enhance payload efficacy and reduce toxicity compared to traditional cytotoxic agents.
- Accelerated translation of ADC research into clinical trials for ovarian, endometrial, and cervical cancers can significantly improve tumor response, survival, and quality of life.
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