Design Synthesis and Testing in Silico of New Antibody Drug Conjugate of Neratinib

Overview

Antibody-drug conjugates (ADCs) offer significant advantages over traditional cancer therapies by enabling the targeted delivery of potent cytotoxic small-molecule drugs (payloads), such as DNA-damaging agents and microtubule disruptors, through the specificity of monoclonal antibodies (mAbs) to cancer cells. By selectively delivering the drug to the site of action, much of the systemic exposure is minimized, as the drug is only activated once the mAb finds its associated antigen in the tumor microenvironment and the linker is cleaved. However, these current ADCs face challenges such as off-target toxicity due to the bystander killing effect and high systemic toxicity due to the potency of its payloads which limits dosing and compromises organ function. Small molecule tyrosine kinase inhibitors (TKIs) present a promising alternative to these potent ADCs as an anti-cancer therapy, their mechanism of action involves the inhibition of tyrosine kinases by blocking the tyrosine substrate from the active site and inhibiting phosphorylation, leading to inhibition of tumor growth and inducing apoptosis. However, despite their selectivity for tyrosine kinases, TKIs often suffer from off-target toxicity when delivered non-selectively, leading to side effects such as diarrhea, fatigue, rash, and potential cardiac and thyroid complications. In this study, We have developed a novel ADC that employs Trastuzumab, a HER2-specific monoclonal antibody, linked to the pan-HER inhibitor Neratinib via a cleavable valine-citrulline linker. Neratinib being a pan-HER inhibitor also addresses potential resistance mechanisms, such as dimerization. The selective delivery of Neratinib through the proposed ADC aims to retain its potent anti-cancer properties while mitigating its off-target side effects. This strategy offers dual-inhibition of HER2 receptor, overcoming the limitations of highly cytotoxic non-specific payloads and non-targeted delivery of kinase inhibitors.