Reference Detail

Ref Type

Journal Article

PMID

(39082679)

Authors

Yang Y, Suhasini AN, Jiang Z, Liu N, Rosconi M, Zhang B, Li Y, Dudgeon D, Seong C, Kim S, Rafique A, Huang T, Bhosle S, Krueger P, Ullman E, Olson W, Lin JC, Shen Y, Daly C

Title

A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	84	13	2024 Jul 02	2169-2180	Cancer Res

URL

Abstract Text

The receptor tyrosine kinase FGFR3 is frequently mutated in bladder cancer and is a validated therapeutic target. Although pan-FGFR tyrosine kinase inhibitors (TKI) have shown clinical efficacy, toxicity and acquired resistance limit the benefit of these agents. While antibody-based therapeutics can offer superior selectivity than TKIs, conventional ligand-blocking antibodies are usually ineffective inhibitors of constitutively active receptor tyrosine kinases. Furthermore, the existence of multiple oncogenic variants of FGFR3 presents an additional challenge for antibody-mediated blockade. Here, we developed a tetravalent FGFR3×FGFR3 bispecific antibody that inhibited FGFR3 point mutants and fusion proteins more effectively than any of the conventional FGFR3 antibodies that we produced. Each arm of the bispecific antibody contacted two distinct epitopes of FGFR3 through a cis mode of binding. The antibody blocked dimerization of the most common FGFR3 oncogenic variant (S249C extracellular domain mutation) and inhibited the function of FGFR3 variants that are resistant to pan-FGFR TKIs. The antibody was highly effective in suppressing growth of FGFR3-driven tumor models, providing efficacy comparable to that of the FDA-approved TKI erdafitinib. Thus, this bispecific antibody may provide an effective approach for broad and highly selective inhibition of oncogenic FGFR3 variants. Significance: Development of a bispecific antibody that broadly inhibits gain-of-function FGFR3 variants provides a therapeutic strategy to target tumors with oncogenic FGFR3 point mutations and fusions, a particularly difficult case for antibody blockade.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
R3-altibody	R3-altibody	5	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
R3-altibody		R3 altibody	FGFR3 Antibody 4	R3-altibody is a tetravalent bispecific antibody targeting FGFR3, which potentially inhibits Fgfr3 dimerization, downstream signaling, and tumor growth (PMID: 39082679).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR3 S249C FGFR3 V555M	Advanced Solid Tumor	resistant	Fexagratinib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line expressing FGFR3 S249C and V555M was resistant to AZD4547 in culture (PMID: 39082679).	39082679
FGFR3 S249C FGFR3 V555M	Advanced Solid Tumor	sensitive	R3-altibody	Preclinical - Cell culture	Actionable	In a preclinical study, R3-altibody inhibited Fgfr3 downstream signaling and growth in a cell line expressing FGFR3 S249C and V555M in culture (PMID: 39082679).	39082679
FGFR3 S249C FGFR3 V555L	Advanced Solid Tumor	resistant	Fexagratinib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line expressing FGFR3 S249C and V555L was resistant to AZD4547 in culture (PMID: 39082679).	39082679
FGFR3 S249C	lung squamous cell carcinoma	sensitive	R3-altibody	Preclinical - Pdx	Actionable	In a preclinical study, R3-altibody inhibited tumor growth in a patient-derived xenograft (PDX) model of lung squamous cell carcinoma harboring FGFR3 S249C (PMID: 39082679).	39082679
FGFR3 S249C FGFR3 V555L	Advanced Solid Tumor	sensitive	R3-altibody	Preclinical - Cell culture	Actionable	In a preclinical study, R3-altibody inhibited Fgfr3 downstream signaling and growth in a cell line expressing FGFR3 S249C and V555L in culture (PMID: 39082679).	39082679
FGFR3 S249C	bladder urothelial carcinoma	sensitive	R3-altibody	Preclinical - Cell line xenograft	Actionable	In a preclinical study, R3-altibody inhibited Fgfr3 dimerization and proliferation in a urothelial carcinoma cell line harboring FGFR3 S249C in culture and induced tumor regression in a cell line xenograft model (PMID: 39082679).	39082679
FGFR3 S249C FGFR3 V555M	Advanced Solid Tumor	resistant	Erdafitinib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line expressing FGFR3 S249C and V555M was resistant to Balversa (erdafitinib) in culture (PMID: 39082679).	39082679
FGFR3 S249C FGFR3 V555L	Advanced Solid Tumor	resistant	Erdafitinib	Preclinical - Cell culture	Actionable	In a preclinical study, a cell line expressing FGFR3 S249C and V555L was resistant to Balversa (erdafitinib) in culture (PMID: 39082679).	39082679
FGFR3 S249C	Advanced Solid Tumor	sensitive	R3-altibody	Preclinical - Cell culture	Actionable	In a preclinical study, R3-altibody inhibited Fgfr3 dimerization and downstream signaling and decreased proliferation in a cell line expressing FGFR3 S249C in culture (PMID: 39082679).	39082679