Preclinical Comparison of Two CD3xB7H4 Bispecific Antibodies for Solid Tumor Therapy Reveals CD3 Affinity-Dependent Potency and Tolerability Tradeoffs
Louise A. Koopman, Farshid Alemdehy, Stefanie A.H. de Poot, Madelon Paauwe, Wenyi Wang, Kaya R. Epstein, Edward N. van den Brink, Andrea Gorlani, Dennis Verzijl, Marcel Brandhorst, Patrick Franken, Laura Smits-de Vries, Ellis Gielen, Theo S. Plantinga, Mischa Houtkamp, Patrick J. Engelberts, Frederikke Lihme Egerod, Craig J. Thalhauser, Sieto Bosgra, Sarah B. Gitto, Daniel J. Powell, Joshua T. Gamse, Marije B. Overdijk, Esther C.W. BreijAbstract
The immune checkpoint protein B7H4 is overexpressed in tumors compared to normal tissues, making it an attractive target for cancer immunotherapy. Here, we compare two B7H4-targeting CD3 bispecific antibodies (bsAbs) with different CD3 affinities across in vitro and in vivo characterization studies. In vitro, the CD3xB7H4 bsAb variant with higher CD3 affinity showed greater potency for tumor cell killing and cytokine secretion than the lower affinity variant. In nonclinical toxicology assessments in cynomolgus monkeys, the CD3xB7H4 bsAb variant with lower CD3 affinity induced less cytokine secretion and was tolerated at a higher maximum plasma concentration. Both CD3xB7H4 bsAbs demonstrated antitumor activity in vivo in an ovarian cancer patient-derived xenograft (PDX) mouse model and ex vivo in dissociated primary human ovarian tumor samples. These results demonstrate that increased CD3 affinity enhances cytotoxic potency but results in cytokine secretion at lower antibody concentrations in vitro and in vivo, highlighting an important design trade-off in CD3 bsAb development. The therapeutic potential of CD3xB7H4 bsAbs, particularly in relation to CD3 affinity, warrants further investigation in the clinic.