Half‐life extension of single‐domain antibody–drug conjugates by albumin binding moiety enhances antitumor efficacy
Quanxiao Li,
Yu Kong,
Yuxuan Zhong,
Ailing Huang,
Tianlei Ying,
Yanling Wu
Affiliations
Quanxiao Li
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology Shanghai Institute of Infectious Disease and Biosecurity Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection Shanghai Engineering Research Center for Synthetic Immunology Department of medical microbiology and parasitology, School of Basic Medical Sciences Fudan University Shanghai China
Yu Kong
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology Shanghai Institute of Infectious Disease and Biosecurity Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection Shanghai Engineering Research Center for Synthetic Immunology Department of medical microbiology and parasitology, School of Basic Medical Sciences Fudan University Shanghai China
Yuxuan Zhong
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology Shanghai Institute of Infectious Disease and Biosecurity Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection Shanghai Engineering Research Center for Synthetic Immunology Department of medical microbiology and parasitology, School of Basic Medical Sciences Fudan University Shanghai China
Ailing Huang
College of Life Sciences Hebei Agricultural University Baoding China
Tianlei Ying
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology Shanghai Institute of Infectious Disease and Biosecurity Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection Shanghai Engineering Research Center for Synthetic Immunology Department of medical microbiology and parasitology, School of Basic Medical Sciences Fudan University Shanghai China
Yanling Wu
MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology Shanghai Institute of Infectious Disease and Biosecurity Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection Shanghai Engineering Research Center for Synthetic Immunology Department of medical microbiology and parasitology, School of Basic Medical Sciences Fudan University Shanghai China
Abstract Single‐domain antibody–drug conjugates (sdADCs) have been proven to have deeper solid tumor penetration and intratumor accumulation capabilities due to their smaller size compared with traditional IgG format ADCs. However, one of the key challenges for improving clinical outcomes of sdADCs is their abbreviated in vivo half‐life. In this study, we innovatively fused an antihuman serum albumin (αHSA) nanobody to a sdADCs targeting oncofetal antigen 5T4, conferring serum albumin binding to enhance the pharmacokinetic profiles of sdADCs. The fusion protein was conjugated with monomethyl auristatin E (MMAE) at s224c site mutation. The conjugate exhibited potent cytotoxicity against various tumor cells. Compared with the nonalbumin‐binding counterparts, the conjugate exhibited a 10‐fold extended half‐life in wild‐type mice and fivefold prolonged serum half‐life in BxPC‐3 xenograft tumor models as well as enhanced tumor accumulation and retention in mice. Consequently, n501–αHSA–MMAE showed potent antitumor effects, which were comparable to n501–MMAE in pancreatic cancer BxPC‐3 xenograft tumor models; however, in human ovarian teratoma PA‐1 xenograft tumor models, n501–αHSA–MMAE significantly improved antitumor efficacy. Moreover, the conjugate showed mitigated hepatotoxicity. In summary, our results suggested that fusion to albumin‐binding moiety as a viable strategy can enhance the therapeutic potential of sdADCs through optimized pharmacokinetics.
