Related Experiment Video
Updated: Apr 5, 2026
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Redesigning a Monospecific Anti-FGFR3 Antibody to Add Selectivity for FGFR2 and Expand Antitumor Activity
Yiyuan Yin1, Stevan Djakovic2, Scot Marsters2
1Department of Antibody Engineering, Genentech, Inc., South San Francisco, California.
Abstract:
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.
Insights
Researchers engineered a cancer therapy antibody to target fibroblast growth factor receptors (FGFRs) 3 and 2. This dual-specificity antibody effectively inhibited tumor growth in mice, offering refined therapeutic potential.
Area of Science:
- Oncology
- Immunology
- Structural Biology
Background:
- Fibroblast growth factor receptors (FGFRs) are implicated in various human cancers.
- Targeting FGFR1 and FGFR4 poses safety risks due to their roles in metabolic functions.
- FGFR2 and FGFR3 inhibition may offer therapeutic benefits with fewer side effects.
Purpose of the Study:
- To redesign a monospecific anti-FGFR3 antibody into a dual-specific antibody targeting FGFR3 and FGFR2.
- To engineer antibodies that spare FGFR1 and FGFR4, minimizing potential safety concerns.
- To evaluate the therapeutic efficacy of the engineered dual-specific antibodies in preclinical cancer models.
Main Methods:
- Structure-guided phage display was used to modify a monospecific anti-FGFR3 antibody (R3Mab).
- Antibody variants were screened for dual specificity against FGFR3 and FGFR2, while sparing FGFR1 and FGFR4.
- X-ray crystallography was employed to analyze antibody-epitope interactions.
- In vivo efficacy was assessed using human tumor xenografts in mice.
Main Results:
- Engineered antibodies demonstrated dual specificity for FGFR3 and FGFR2, with reduced affinity for FGFR4.
- The dual-specific antibodies effectively blocked FGF binding and inhibited downstream signaling pathways.
- Significant efficacy was observed in mouse models against human tumor xenografts overexpressing FGFR3 or FGFR2.
Conclusions:
- Monospecific antibodies can be precisely engineered for dual or altered target specificities.
- Tailored FGFR-targeting antibodies show promise for cancer therapy with potentially improved safety profiles.
- This approach refines therapeutic strategies by expanding the utility of antibody-based FGFR inhibition.
