Abstract

 Antibody-drug conjugates (ADCs) have emerged as a promising class of targeted cancer therapeutics, combining the specificity of monoclonal antibodies with the potency of cytotoxic drugs. A critical component of ADCs is the linker, which connects the drug to the antibody and plays a vital role in determining the pharmacokinetics, stability, and release of the drug payload. Traditional linkers often face challenges such as premature release or insufficient stability in the bloodstream. 

Tetrazine ligation chemistry offers a novel approach for designing cleavable linkers in ADCs. This bio-orthogonal reaction enables rapid and selective conjugation under mild conditions, allowing for the incorporation of trigger-responsive elements within the linker structure. The resulting linkers can be engineered to release the drug payload in response to specific stimuli present in the tumor microenvironment, such as reductive conditions or enzymatic activity.

In this talk, we will explore the principles and advantages of tetrazine ligation chemistry for ADC linker design. We will discuss the synthesis and characterization of tetrazine derivatives for click-to-release chemistry, and their efficacy in controlled drug release. Through the systematic study of tetrazine ligation, we aim to develop Immune stimulating antibody conjugates (ISACs) with enhanced therapeutic efficacies and reduced off-target toxicity.