Abstract
Antibody-drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo; however, the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable antitumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior antitumor activity. Given that the 5T4-PBD possessed both potent antitumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4+ cancer indications. Mol Cancer Ther; 16(8); 1576-87. ©2017 AACR.
Highlights
Antibody–drug conjugates (ADC) represent a promising therapeutic approach to effectively treat cancer while reducing drugrelated toxicities by combining the specificity of an antibody with the potency of cytotoxic agents
To confirm these findings and to focus on cancer types with the highest incidence of 5T4 expression, extensive IHC of tumor microarrays and tumor samples as well as normal tissue arrays was conducted. 5T4 was broadly expressed in tumor microarrays and clinical tumor samples representing a number of cancer types, with the highest incidence in gastric cancer, non–small cell lung cancer (NSCLC), and head and neck squamous cell carcinoma (HNSCC; Fig. 1A)
MEDI0641 is a 5T4-targeting ADC conjugated with a PBD payload that is capable of inducing significant antitumor activity, including durable regressions in tumor models with varying intensity and heterogeneity of 5T4 expression
Summary
Antibody–drug conjugates (ADC) represent a promising therapeutic approach to effectively treat cancer while reducing drugrelated toxicities by combining the specificity of an antibody with the potency of cytotoxic agents (reviewed in refs. 1–3). Antibody–drug conjugates (ADC) represent a promising therapeutic approach to effectively treat cancer while reducing drugrelated toxicities by combining the specificity of an antibody with the potency of cytotoxic agents The warhead exits the lysosome where it can bind to its target, typically either microtubules or DNA, depending on its mechanism of action. The binding of these cytotoxic agents to their targets results in cell-cycle arrest that subsequently leads to cell death. Given the generally high potency of cytotoxics most commonly used in ADCs, it is important to identify targets exhibiting both good expression in tumors and limited normal tissue expression to reduce the possibility of on-target toxicity
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