Tumor Microenvironment-Responsive Antibody Fragment-Cleavable PEGylated Drug Conjugates (AFCDC) for Improved Tumor Penetration and Antitumor Efficacy

  • J Med Chem. 2026 May 14;69(9):10169-10182. doi: 10.1021/acs.jmedchem.5c03215.
Xin Wang  1 ,  Xiaoyu Hou  1 ,  Linzhi Tan  1 ,  Canpu Chen  1 ,  Liying Chang  1 ,  Boyang Han  2 ,  Yunqi Xing  1 ,  Zhiying Zeng  1 ,  Ziting Zhou  3 ,  Qiang Lu  1 ,  Leyi Xie  1 ,  Ziyi Lu  1 ,  Kerui Zhao  1 ,  Baoshan Cao  4 ,  Tao Liu  1 ,  Yong Wang  1
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
  • 2. Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467, United States.
  • 3. School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100084, China.
  • 4. Cancer Center, Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing 100191, China.
PMID: 42055598 DOI: 10.1021/acs.jmedchem.5c03215
Abstract

Antibody-drug conjugates (ADCs) are important Cancer therapeutics, yet efficacy in solid tumors is limited by poor penetration: the large size (∼150 kDa) restricts vascular extravasation and stromal diffusion, and strong bivalent IgG-antigen binding creates a binding-site barrier. Antibody fragment-drug conjugates (FDCs) penetrate better but clear rapidly, compromising retention. We developed a programmable Antibody Fragment-Cleavable PEGylated Drug Conjugate (AFCDC) platform enabling site-specific dual conjugation through genetically encoded bifunctional noncanonical Amino acids, pTAF to attach cytotoxic payloads, and MMP2-cleavable PEG chains. PEGylation extends the systemic half-life, while tumor proteases remove PEG to yield smaller fragment-payload conjugates with improved tissue penetration. AFCDC improves intratumoral penetration, pharmacokinetics, and efficacy in HER2-positive tumor models. Under the evaluated regimen, AFCDC demonstrated enhanced activity over T-DXd in the NCI-N87 xenografts. Overall, AFCDC resolves the antibody fragment trade-off, providing a strategy compatible with multiple formats and payloads to enhance the ADC efficacy in solid tumors.

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