TY  - JOUR
AU  - Zekri, Latifa
AU  - Lutz, Martina Svenja
AU  - Prakash, Nisha
AU  - Manz, Timo
AU  - Klimovich, Boris
AU  - Mueller, Stefanie
AU  - Hoerner, Sebastian
AU  - Hagelstein, Ilona
AU  - Engel, Monika
AU  - Chashchina, Anna
AU  - Pfluegler, Martin
AU  - Heitmann, Jonas
AU  - Jung, Gundram
AU  - Salih, Helmut
TI  - An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers.
JO  - Molecular therapy
VL  - 31
IS  - 4
SN  - 1525-0016
CY  - New York, NY
PB  - Nature Publ. Group
M1  - DKFZ-2023-00360
SP  - 1033-1045
PY  - 2023
N1  - 2023 Apr 5;31(4):1033-1045
AB  - T cell-based immunotherapy has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions remain rare, particularly in gastrointestinal cancers like colorectal cancer (CRC). B7-H3 is overexpressed in multiple cancer entities including CRC on both, tumor cells and tumor vasculature, the latter facilitating influx of effector cells into the tumor site upon therapeutic targeting. We generated a panel of T cell-recruiting B7-H3xCD3 bispecific antibodies (bsAbs) and show that targeting a membrane-proximal B7-H3 epitope allows for a 100-fold reduction of CD3 affinity. In vitro, our lead compound CC-3 showed superior tumor cell killing, T cell activation, proliferation and memory formation, whereas undesired cytokine release was reduced. In vivo, CC-3 mediated potent antitumor activity in three independent models using immunocompromised mice adoptively transferred with human effector cells with regard to prevention of lung metastasis and flank tumor growth as well as elimination of large established tumors. Thus, fine-tuning of both, target and CD3 affinities as well as binding epitopes allowed for the generation of a B7-H3xCD3 bsAb with promising therapeutic activity. CC-3 is presently undergoing GMP production to enable evaluation in a clinical 'first in human' study in CRC.
LB  - PUB:(DE-HGF)16
C6  - pmid:36793213
DO  - DOI:10.1016/j.ymthe.2023.02.010
UR  - https://inrepo02.dkfz.de/record/271007
ER  -