Redesigning a Monospecific Anti-FGFR3 Antibody to Add Selectivity for FGFR2 and Expand Antitumor Activity.
FGF receptors (FGFR) are attractive candidate targets for cancer therapy because they are dysregulated in several human malignancies. FGFR2 and FGFR3 can be inhibited potentially without disrupting adult tissue homeostasis. In contrast, blocking the closely related FGFR1 and FGFR4, which regulate specific metabolic functions, carries a greater safety risk. An anti-FGFR3 antibody was redesigned here to create function-blocking antibodies that bind with dual specificity to FGFR3 and FGFR2 but spare FGFR1 and FGFR4. R3Mab, a previously developed monospecific anti-FGFR3 antibody, was modified via structure-guided phage display and acquired additional binding to FGFR2. The initial variant was trispecific, binding tightly to FGFR3 and FGFR2 and moderately to FGFR4, while sparing FGFR1. The X-ray crystallographic structure indicated that the antibody variant was bound to a similar epitope on FGFR2 as R3Mab on FGFR3. The antibody was further engineered to decrease FGFR4-binding affinity while retaining affinity for FGFR3 and FGFR2. The resulting dual-specific antibodies blocked FGF binding to FGFR3 and FGFR2 and inhibited downstream signaling. Moreover, they displayed efficacy in mice against human tumor xenografts overexpressing FGFR3 or FGFR2. Thus, a monospecific antibody can be exquisitely tailored to confer or remove binding to closely related targets to expand and refine therapeutic potential.
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California.
Yiyuan
Y
Yin
Department of Cancer Immunology, Genentech, Inc., South San Francisco, California.
Stevan
S
Djakovic
Department of Cancer Immunology, Genentech, Inc., South San Francisco, California.
Scot
S
Marsters
Department of Translational Oncology, Genentech, Inc., South San Francisco, California.
Janet
J
Tien
Department of Translational Oncology, Genentech, Inc., South San Francisco, California.
Jing
J
Peng
Department of Translational Oncology, Genentech, Inc., South San Francisco, California.
Jarrod
J
Tremayne
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California.
Genee
G
Lee
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California.
Richard M
RM
Neve
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California.
Yan
Y
Wu
Department of Translational Oncology, Genentech, Inc., South San Francisco, California.
Mark
M
Merchant
Department of Cancer Immunology, Genentech, Inc., South San Francisco, California. pjc@gene.com aa@gene.com.
Avi
A
Ashkenazi
Department of Antibody Engineering, Genentech, Inc., South San Francisco, California. pjc@gene.com aa@gene.com.
Paul J
PJ
Carter
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D062105:Molecular Docking Simulation; D011485:Protein Binding; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3