Strategies in antibody-drug conjugate design to improve precision targeting and maximize therapeutic index

Antibody – drug conjugates (ADCs) enable tumor-targeted delivery of highly potent cytotoxic payloads. Despite major developments in the field, clinical success can be limited by tumor heterogeneity, intratumoral ADC/payload distribution, and off-target toxicity. This review discusses how strategic design of ADCs can overcome these challenges, including antibody engineering, appropriate payload and tumor-selective release triggers, and advancements in conjugation technologies. For example, advances in biparatopic and bispecific antibodies can overcome heterogeneous tumor target expression, improve internalization, and limit on-target/off tumor liabilities. Strategic design of dosing regimens can overcome challenges of tissue penetration barriers. Approaches such as pH-dependent binding or protease-­activated antibodies can increase selectivity of payload delivery. Conjugation and tumor-­selective release technologies can limit disposition of highly cytotoxic payload in circulation to maximize the benefit-risk profile of an ADC. Collectively, these advancements are aimed at developing more precise and effective treatments of heterogeneous cancers with a wider therapeutic index.

What you will learn

01

How biparatopic and bispecific ADCs overcome heterogeneous tumor antigen expression

02

How dosing strategies and conditional activation improve tumor penetration and selectivity

03

How stable conjugation and tumor-selective linkers limit premature payload release

Key interests

Antibody–drug conjugates Tumor heterogeneity Bispecific ADCs Conditional activation Fc silencing Site-specific conjugation Cleavable linkers Therapeutic index

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