Preclinical development of a novel CD47 nanobody with less toxicity and enhanced anti-cancer therapeutic potential

• Main Authors: Linlin Ma, Min Zhu, Junwei Gai, Guanghui Li, Qing Chang, Peng Qiao, Longlong Cao, Wanqing Chen, Siyuan Zhang, Yakun Wan
• Format: Article
• Language: English
• Published: BMC 2020-01-01
• Series: Journal of Nanobiotechnology
• Subjects: CD47; Immunotherapy; Nanobody; Bispecific antibody
• Online Access: https://doi.org/10.1186/s12951-020-0571-2

Abstract Background CD47, the integrin-related protein, plays an important role in immune resistance and escape of tumor cells. Antibodies blocking the CD47/SIRPα signal pathway can effectively stimulate macrophage-mediated phagocytosis of tumor cells, which becomes a promising approach for tumor immunotherapy. Nanobodies (Nbs) derived from camelid animals are emerging as a new force in antibody therapy. Results HuNb1-IgG4, an innovative anti-CD47 nanobody, was developed with high affinity and specificity. It effectively enhanced macrophage-mediated phagocytosis of tumor cells in vitro and showed potent anti-ovarian and anti-lymphoma activity in vivo. Importantly, HuNb1-IgG4 did not induce the agglutination of human red blood cells (RBCs) in vitro and exhibited high safety for hematopoietic system in cynomolgus monkey. In addition, HuNb1-IgG4 could be produced on a large scale in CHO-S cells with high activity and good stability. Also, we established anti-CD47/CD20 bispecific antibody (BsAb) consisted of HuNb1 and Rituximab, showing more preference binding to tumor cells and more potent anti-lymphoma activity compared to HuNb1-IgG4. Conclusions Both of HuNb1-IgG4 and anti-CD47/CD20 BsAb are potent antagonists of CD47/SIRPα pathway and promising candidates for clinical trials.