Linker Design Impacts Antibody-Drug Conjugate Pharmacokinetics and Efficacy via Modulating the Stability and Payload Release Efficiency.

Dian Su,Donglu Zhang

doi:10.3389/fphar.2021.687926

Abstract

The development of antibody-drug conjugates (ADCs) has significantly been advanced in the past decade given the improvement of payloads, linkers and conjugation methods. In particular, linker design plays a critical role in modulating ADC stability in the systemic circulation and payload release efficiency in the tumors, which thus affects ADC pharmacokinetic (PK), efficacy and toxicity profiles. Previously, we have investigated key linker parameters such as conjugation chemistry (e.g., maleimide vs. disulfide), linker length and linker steric hindrance and their impacts on PK and efficacy profiles. Herein, we discuss our perspectives on development of integrated strategies for linker design to achieve a balance between ADC stability and payload release efficiency for desired efficacy in antigen-expressing xenograft models. The strategies have been successfully applied to the design of site-specific THIOMABTM antibody-drug conjugates (TDCs) with different payloads. We also propose to conduct dose fractionation studies to gain guidance for optimal dosing regimens of ADCs in pre-clinical models.

Highlights

To date, ten antibody-drug conjugates (ADCs) have been approved by the Food and Drug Administration (FDA) with four approved by the European Medicines Agency (EMA) (HafeezTM et al, 2020; Joubert et al, 2020)
We discovered that a shorter linker typically results in better ADC stability by tethering the payload further inside the steric shield of the antibody relative to a longer linker
Good systemic ADC stability is desired so that linkerpayloads are protected from hydrolysis in circulation

Summary

Introduction

Ten antibody-drug conjugates (ADCs) have been approved by the Food and Drug Administration (FDA) with four approved by the European Medicines Agency (EMA) (HafeezTM et al, 2020; Joubert et al, 2020). (sacituzumab govitecan-hziy), Polivy® (polatuximab vendotin) Enhertu® (trastuzumab deruxtecan), Adcetris® (brentuximab vendotin), Kadcyla® (ado-trastuzumab emtansine), and Besponsa®. (inotuzumab ozogamicin) have increased interest in expanding the applications of ADCs. ADCs consist of an antibody that targets a disease-associated antigen(s) and a payload drug that is connected to the antibody via a chemical linker. The approved ADC drugs utilize both cleavable and non-cleavable linkers that are connected to lysines, inter-chain cysteines, or site-specific cysteines (Joubert et al, 2020; Zhao et al, 2020). Linkers are made of proteasesensitive peptides (e.g., Enhertu® (Ogitani et al, 2016), Polivy® (Deeks, 2019), Adcetris® (Doronina et al, 2003), ZynlontaTM (Zammarchi et al, 2018) or acid-labile components (e.g., Besponsa® (Shor et al, 2015)

Methods

Conclusion