Antibodies: Cornerstone of ADC precision and efficacy

Antibody-drug conjugates (ADCs) continue to evolve as a therapeutic modality that marries cytotoxic potency of small molecule drugs with targeted delivery. Considerable effort has historically focused on payload potency and linker chemistry, yet the decisive factor in determining ADC success is often the most underappreciated: the antibody itself. The antibody dictates the “where, when, and how” of action. It defines the therapeutic index by directing cytotoxic payloads toward malignant cells while ideally sparing normal tissues.

Tumour targeting
A recurring obstacle lies in so-called dirty targets, antigens expressed both in tumours and in healthy tissues. In these contexts, strategies such as affinity tuning, dual-targeting, or conditional activation become essential to balance selectivity and safety. The complexity is compounded by additional variables –including antigen density, internalisation efficiency, accessibility, and cross-reactivity – which must be resolved early in discovery. Clinical experience has shown that inadequately optimised antibodies can undermine otherwise elegant ADC architectures, leading to suboptimal efficacy or unacceptable toxicity.
Advances in antibody engineering now offer promising solutions. Bispecific and biparatopic antibodies can enforce tumour selectivity and accelerate internalisation. Conditionally active designs – exploiting pH-sensitivity, protease-cleavability, or affinity modulation – further refine the therapeutic window by minimising systemic exposure. Together, these approaches represent a deliberate shift from “antibody as simple carrier” toward “antibody as engineered determinant of outcome.”

New formats
Exploration of TCR-mimic (TCRm) antibodies extends this logic to the intracellular antigen space, enabling ADC development against peptide-MHC complexes. While this broadens the target landscape, formidable challenges remain: low epitope density, inefficient presentation, and heightened off-target risk. To succeed, TCRm-based ADCs will demand unprecedented antibody precision, achieved through rigorous screening and structure-guided engineering. Their eventual clinical viability may hinge on pairing with ultra-potent payloads and highly controlled activation mechanisms.

Looking forward, the role of antibodies in ADCs will expand as development moves beyond oncology into autoimmune and inflammatory diseases. The next wave of ADC innovation will therefore depend less on “what is carried” and more on “who carries it”– with modern antibody engineering positioned as the decisive force shaping efficacy, safety, and clinical translation.

This article from Dr Oliver Hill, Senior Director of Protein Engineering, YUMAB GmbH, was originally published in the Special CDMOs & CROs as part of European Biotechnology Magazine Autumn 2025.