From Payload‐First Toward Dual‐Mechanism Antibody–Drug Conjugates

Abstract

Antibody-drug conjugates (ADCs) are often described as simple carriers that shuttle cytotoxic payloads to tumors. However, many backbones, exemplified by trastuzumab, are potent biologics whose pharmacology is eroded by conjugation. In this Perspective, we introduce the concept of an antibody exposure deficit. This represents the systematic reduction in both antibody mass and systemic exposure delivered by an ADC relative to its approved unconjugated monoclonal antibody. We show how payload type, drug-toantibody ratio (DAR), linker and payload-linker hydrophobicity, and conjugation architecture together drive this deficit. Sitespecific DAR 1 formats can mitigate this deficit, unlike higher-DAR constructs such as antibody-polymer conjugates, where the monoclonal antibody serves primarily as a carrier for effective payloads. This defines a landscape of ADC design to which fragment crystallizable (Fc) activity modulation adds further complexity. Altogether, these strategies span the continuum of possible ADC constructs.

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BibTeX RIS

BibTeX

@article{pivot2026from,
  title = {{From Payload‐First Toward Dual‐Mechanism Antibody–Drug Conjugates}},
  author = {Xavier Pivot and Sebastian Jung and Sébastien Harlepp and Alexandre Detappe},
  journal = {Advanced Materials},
  year = {2026},
  month = jun,
  doi = {10.1002/adma.74387},
  url = {https://univoak.hal.science/hal-05750641v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - From Payload‐First Toward Dual‐Mechanism Antibody–Drug Conjugates
AU  - Xavier Pivot
AU  - Sebastian Jung
AU  - Sébastien Harlepp
AU  - Alexandre Detappe
PY  - 2026
DA  - 2026/06/30
JO  - Advanced Materials
DO  - 10.1002/adma.74387
UR  - https://univoak.hal.science/hal-05750641v1
AB  - Antibody-drug conjugates (ADCs) are often described as simple carriers that shuttle cytotoxic payloads to tumors. However, many backbones, exemplified by trastuzumab, are potent biologics whose pharmacology is eroded by conjugation. In this Perspective, we introduce the concept of an antibody exposure deficit. This represents the systematic reduction in both antibody mass and systemic exposure delivered by an ADC relative to its approved unconjugated monoclonal antibody. We show how payload type, drug-toantibody ratio (DAR), linker and payload-linker hydrophobicity, and conjugation architecture together drive this deficit. Sitespecific DAR 1 formats can mitigate this deficit, unlike higher-DAR constructs such as antibody-polymer conjugates, where the monoclonal antibody serves primarily as a carrier for effective payloads. This defines a landscape of ADC design to which fragment crystallizable (Fc) activity modulation adds further complexity. Altogether, these strategies span the continuum of possible ADC constructs.
SN  - 0935-9648
SN  - 1521-4095
ER  -

Abstract

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