Abstract P141: Preclinical characterization of LOX-24350, a highly potent and isoform-selective FGFR3 inhibitor

Ballard, Joshua A.; Kercher, Timothy; Abraham, David; Brecht, Ryan; Brooks, Nathan; Buckles, Thomas; Bume, Desta; Busha, David A.; Cedervall, Ernst Peder; Condroski, Kevin R.; Ebata, Kevin; Gharbi, Severine; Hazlitt, Robert A.; Morales, Tony; Patel, Nisha R.; Podoll, Jessica D.; Urkalan, Kaveri; Villalain, Sandra Gomez; Walls, Shane; Watson, Faith D.; Yang, Pinchen; Brandhuber, Barbara J.; Andrews, Steven W.

doi:10.1158/1535-7163.targ-21-p141

Cited by 5 publications

(2 citation statements)

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“…Although an FGFR3-selective TKI would very likely be better tolerated than the pan-FGFR TKIs, the high degree of homology of the FGFR family tyrosine kinase domains has hampered the development of such agents. Recently, however, an FGFR-3–selective inhibitor (LOXO-435) has been disclosed ( 23 ) and is currently in a Phase 1 clinical trial.…”

Section: Discussionmentioning

confidence: 99%

A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants

Yang,

Suhasini,

Jiang

et al. 2024

Cancer Research

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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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Section: Discussionmentioning

confidence: 99%

A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants

Yang,

Suhasini,

Jiang

et al. 2024

Cancer Research

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“…114 Many other emerging treatment options remain under investigation for bladder cancer, including soluble EphB4-human serum albumin, 115 bicycle conjugates, 116 and FGFR3 specific inhibitors. 117 Results of such ongoing developments are eagerly awaited.…”

Section: Emerging and Novel Treatmentsmentioning

confidence: 99%

Advances in diagnosis and treatment of bladder cancer

Lopez-Beltran,

Cookson,

Guercio

et al. 2024

BMJ

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Bladder cancer remains a leading cause of cancer death worldwide and is associated with substantial impacts on patient quality of life, morbidity, mortality, and cost to the healthcare system. Gross hematuria frequently precedes the diagnosis of bladder cancer. Non-muscle-invasive bladder cancer (NMIBC) is managed initially with transurethral resection of a bladder tumor (TURBT), followed by a risk stratified approach to adjuvant intravesical therapy (IVe), and is associated with an overall survival of 90%. However, cure rates remain lower for muscle invasive bladder cancer (MIBC) owing to a variety of factors. NMIBC and MIBC groupings are heterogeneous and have unique pathological and molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers and luminal and basal molecular subtypes of MIBC with distinct treatment responses. For NMIBC, IVe immunotherapy (primarily BCG) is the gold standard treatment for high grade and high risk NMIBC to reduce or prevent both recurrence and progression after initial TURBT; novel trials incorporate immune checkpoint inhibitors. IVe gene therapy and combination IVe chemotherapy have recently been completed, with promising results. For localized MIBC, essential goals are improving care and reducing morbidity following cystectomy or bladder preserving strategies. In metastatic disease, advances in understanding of the genomic landscape and tumor microenvironment have led to the implementation of immune checkpoint inhibitors, targeted treatments, and antibody-drug conjugates. Defining better selection criteria to identify the patients most likely to benefit from a specific treatment is an urgent need.

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Current and emerging therapies for Achondroplasia: The dawn of precision medicine

Dardenne¹,

Ishiyama²,

Lin³

et al. 2023

Bioorganic & Medicinal Chemistry

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Abstract P141: Preclinical characterization of LOX-24350, a highly potent and isoform-selective FGFR3 inhibitor

Cited by 5 publications

References 0 publications

A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants

A Tetravalent Bispecific Antibody Selectively Inhibits Diverse FGFR3 Oncogenic Variants

Advances in diagnosis and treatment of bladder cancer

Current and emerging therapies for Achondroplasia: The dawn of precision medicine

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