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    A highly stable human single-domain antibody-drug conjugate exhibits superior penetration and treatment of solid tumors

    Yanling Wu , Quanxiao Li , Yu Kong , Zhi Wang , Cheng Lei , Ji Li , Lulu Ding , Chunyu Wang , Yaping Cheng , Yaozhu Wei , Yuanlin Song , Zhenlin Yang
    Mol Ther . 2022 Apr 22;S1525-0016(22)00242-8.

    The inefficient tumor penetration of therapeutic antibodies has hampered their effective use in treating solid tumors. Here, we report the identification of a fully human single-domain antibody (UdAb), designated as n501, targeting the oncofetal antigen 5T4. The high-resolution crystal structure indicates that n501 adopts a compact structure very similar to that of camelid nanobodies, and binds tightly to all eight leucine-rich repeats of 5T4. Furthermore, the UdAb n501 exhibits exceptionally high stability, with no apparent activity changes over 4 weeks of storage at various temperatures. Importantly, the UdAb-based antibody-drug conjugate (n501-SN38) showed much deeper tumor penetration, significantly higher tumor uptake, and faster accumulation at tumor sites than conventional IgG1-based antibody-drug conjugate (m603-SN38), resulting in improved tumor inhibition. These results highlight the potential of UdAb-based antibody-drug conjugates as a potential class of antitumor therapeutics with characteristics of high stability and strong tumor penetration for the effective treatment of solid tumors.