Antibody Drug Conjugates: Preclinical Considerations.
The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.
Centers for Therapeutic Innovation (CTI), Pfizer Inc., 450 East 29th Street, New York, New York, 10016, USA, gadi.bornstein@pfizer.com.
Gadi G
GG
Bornstein
D000617:Aminoglycosides / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D017277:Drug Approval; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000079982:Gemtuzumab; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000378:metabolism; D014018:Tissue Distribution; D014481:United States; D014486:United States Food and Drug Administration
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D000079982:Gemtuzumab