Exploring Experimental and In Silico Approaches for Antibody-Drug Conjugates in Oncology Therapies

Abstract

Background/objectives: Antibody-drug conjugates are a rapidly evolving class of cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs. This review explores experimental and computational advances in ADC design, focusing on structural elements and optimization strategies.

Methods: We examined recent developments in the mechanisms of action, antibody engineering, linker chemistries, and payload selection. Emphasis was placed on experimental strategies and computational tools, including molecular modeling and AI-driven structure prediction.

Results: ADCs function through both internalization-dependent and -independent mechanisms, enabling targeted drug delivery and bystander effects. The therapeutic efficacy of ADCs depends on key factors: antigen specificity, linker stability, and payload potency. Linkers are categorized as cleavable or non-cleavable, each with distinct advantages. Payloads-mainly tubulin inhibitors and DNA-damaging agents-require extreme potency to be effective. Computational methods have become essential for antibody modeling, developability assessment, and in silico optimization of ADC components, accelerating candidate selection and reducing experimental labor.

Conclusions: The integration of experimental and in silico approaches enhances ADC design by improving selectivity, stability, and efficacy. These strategies are critical for advancing next-generation ADCs with broader applicability and improved therapeutic indices.

Keywords: ADC design; antibody–drug conjugates; cancer; linker; molecular modeling; payload; targeted therapy.

Figure 1

Schematic representation of the components of an antibody–drug conjugate: a monoclonal antibody, a cytotoxic drug, and a molecular linker.

Figure 2

Mechanisms of action of antibody–drug conjugates: (A) targeted drug delivery via antigen–antibody recognition and internalization, leading to apoptosis or necrosis; and (B) bystander killing of adjacent tumor cells through passive diffusion of lipophilic drugs.

Figure 3

General structure of an antibody, which consist of two light chains (L, light, in magenta) and two heavy chains (H, heavy, in cyan and blue). The Fab region comprises the variable domains VH (variable, heavy) and VL (variable, light), along with the constant domains CH1 (constant, heavy) and CL (constant, light). The Fc region consists of the constant domains CH2 and CH3. CDR loops are highlighted in orange.