Effective design and dose predictions for Antibody Drug Conjugates (ADC) through combined efficacy and toxicity modeling

抄録

Objectives: ADCs represent a novel class of targeted and highly potent chemotherapies that have shown promise in cancer regression. Using a tumor targeting monoclonal antibody conjugated to a cytotoxic payload, ADCs are capable of precise targeting and potent efficacy, simultaneously. However, clinical evidence has shown that systemic toxicities can limit their therapeutic window. While efficacy is the key endpoint, much of the ADC toxicity is payload dependent and Hematological toxicities are the most common adverse events[1]. In the current work we present a mechanistic model, with utility in novel ADC development, to quantify efficacy and toxicity to help in payload selection and First-In-Human (FIH) dose recommendations.

Methods: The present model considers the following factors to determine ADC efficacy - 1) Receptor occupancy, 2) Payload cell killing potential, 3) Bystander effect and 4) Dose sensitivity. Our previous work showed that mechanistic modeling can be used for a) payload comparison and b) FIH dose recommendations based on Minimum Efficacious Dose (MED)[2]. In this poster we extend our prior work by considering hematological toxicity due to the payload (caused by plasma exposure) to predict Maximum Tolerable Dose (MTD) based on preclinical evidence and published data from other approved ADCs.

Results: We utilized the developed mechanistic model, to predict combined efficacy and toxicity based FIH dose for the approved ADCs: Trastuzumab deruxtecan (T-Dxd), Trastuzumab emtansine (T-DM1), and Loncastuximab Tesirine using published preclinical data. The model predicted FIH is observed to be close to the clinically recommended doses. In addition, the proposed approach can be used to compare strengths and weaknesses of different payloads on multiple efficacy and toxicity aspects.

Conclusions: Our proposed mechanistic ADC model can be used to answer several key questions like 1) How to choose the right payload for the ADC? 2) What should be the FIH dosing? A combined understanding of efficacy and toxicity is needed for ADCs for payload assessment and informing practical dose range in the clinic.

References 1. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. doi: 10.1080/19420862.2016.1156829

2. Seshasai PC et al, Development of a mechanistic mPBPK/QSP Antibody drug conjugates (ADC) platform model with applications across preclinical, translational and clinical stages of drug development, ACoP 11