Bioanalytical & Pre-Clinical Development Strategies for ADCs
Sanghamitra Bhattacharjee, Senior Scientist, Theramyt Novobiologics Pvt. Ltd
The concept of a “magic bullet” in immune oncology
has been a dream for centuries. Recent technological advances enabled
antibody-drug conjugates to materialize that dream. Approvals of
Brentuximab-vedotin and Trastuzumab-emtansine reveal the potential for
antibody-drug conjugates to offer newer therapeutic avenues for cancer
patients. These antibody drug conjugates (ADCs) are expected to be superior
over either monoclonal antibodies or cytotoxic small molecules. More than thirty ADCs are under clinical development.
We will talk about development of trastuzumab-emtansine as a case study.
Product development strategies for ADCs in general involve selection of an
antibody, a cytotoxic drug, chemical conjugation, linker technology and
effective drug release. Preclinical development includes rodent and primate
studies to decipher two prime aspects that are efficacy and toxicity. Efficacy
studies include pharmacokinetics and pharmacodynamics profiling. Toxicity
indices consist of histopathology, neurologic, ophthalmic examinations and
effect of repeat dosing. Bioanalytical studies include ADC serum ELISA, total
antibody serum ELISA, emtansine plasma LC-MS/MS and immunogenicity testing. In
2008, Lewis Phillips and colleagues published their study that elucidates bio
analytical and preclinical development of trastuzumab-emtansine. They
demonstrated target specific cytotoxicity in trastuzumab resistant HER2
overexpressing tumors with increased linker stability and improved safety
profile in rodents. In 2014, Diana et al. demonstrated that
trastuzumab-emtansine is nearly three times more effective than trastuzumab
alone in inhibiting cell proliferation in vitro while both the drugs showed
comparable levels of ADCC in Her2 overexpressing cell lines. In vivo
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