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Abstract
T-cell engaging bispecific antibodies (biAbs) can mediate potent and specific tumor cell eradication in liquid cancers. Substantial effort has been invested in expanding this concept to solid cancers. To explore their utility in the treatment of ovarian cancer, we built a set of asymmetric biAbs in IgG1-like format that bind CD3 on T cells with a conventional scFv arm and folate receptor 1 (FOLR1) on ovarian cancer cells with a conventional or a chemically programmed Fab arm. For avidity engineering, we also built an asymmetric biAb format with a tandem Fab arm. We show that both conventional and chemically programmed CD3 × FOLR1 biAbs exert specific in vitro and in vivo cytotoxicity toward FOLR1-expressing ovarian cancer cells by recruiting and activating T cells. While the conventional T-cell engaging biAb was curative in an aggressive mouse model of human ovarian cancer, the potency of the chemically programmed biAb was significantly boosted by avidity engineering. Both conventional and chemically programmed CD3 × FOLR1 biAbs warrant further investigation for ovarian cancer immunotherapy.
Highlights
As one of the promising next-generation cancer immunotherapeutics, T-cell engaging bispecific antibodies mediate potent and selective cytotoxicity by targeting tumor cell surface receptors with one arm and by recruiting and activating T cells with the other arm [1, 2]
All share (i) a human IgG1 Fc module with knobs-into-holes mutations for heterodimerization and aglycosylation mutation N297A in the second constant heavy chain domain (CH2), and (ii) a single-chain Fv (scFv) module composed of the variable heavy (VH) and light (VL) chain domains of a humanized and affinity matured version, called v9, of mouse anti-human CD3 monoclonal antibodies (mAbs) UCHT1 [21]
While all biAbs are defined by their ability to bind two antigens, blinatumomab is a biAb that crosslinks effector and target cells for cancer immunotherapy by engaging CD3 on T cells and CD19 on acute lymphoblastic leukemia cells
Summary
As one of the promising next-generation cancer immunotherapeutics, T-cell engaging bispecific antibodies (biAbs) mediate potent and selective cytotoxicity by targeting tumor cell surface receptors with one arm and by recruiting and activating T cells with the other arm [1, 2]. The distinguishing feature of chemically programmed biAbs is the use of a natural or synthetic small molecule rather than an antibody or antibody fragment for tumor cell binding and Asymmetric Bispecific Antibodies Targeting FOLR1 site-specific covalent conjugation to a T-cell engaging antibody or antibody fragment [7,8,9,10]. The concept of chemically programmed biAbs builds on an anticipated wealth of synthetic small molecules derived from chemical libraries or from structure-based design campaigns to bind tumor cell surface receptors with high specificity and affinity
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