Targeting FGFR3 in t(4;14) Mutiple Myeloma: Pre-Clinical Studies of PRO-001, a Novel Anti-FGFR3 Neutralizing Antibody.
Bibliographic record
Abstract
Abstract As with other B-cell malignancies, chromosomal translocations to the immunoglobulin heavy-chain (IgH) locus on chromosome 14q32 are believed to be a hallmark of multiple myeloma (MM), occurring in approximately 50% of patients. Identification of these chromosomal translocations has resulted in the discovery of powerful prognostic tools and novel molecular targets that promise to revolutionize the treatment of this malignancy. Five recurrent translocation partners have been defined, resulting in the dysregulation of the genes encoding cyclin D1 and D3, c-maf, mafB and Fibroblast Growth Factor Receptor 3 (FGFR3) together with MMSET. Genetic analysis of 14q32 translocations in MM has identified distinct groups of patients with separate clinical outcomes supporting a biological correlation of these genes in MM. In particular, the t(4;14) translocation portends a particularly bad prognosis. The association of FGFR3 expression with t(4;14) myeloma and the demonstration of the transforming potential of this receptor tyrosine kinase (RTK), make this a particularly attractive target for drug development for this poor prognosis group. We report here the development of a novel and highly specific anti-FGFR3 neutralizing antibody (PRO-001) isolated from a phage display human combinatorial antibody library. PRO-001 binds with high affinity (Kd=1.3 nM) to FGFR3 in in vitro binding assays and blocks ligand-dependent and independent FGFR3 phosphorylation and signal transduction in cell-based assays. Furthermore, PRO-001 potently inhibits FGFR3-dependent solid tumor growth in mouse xenograft models. We found that PRO-001 bound to, and competed with FGF binding to the surface of FGFR3 on human myeloma cell lines. PRO-001 inhibited FGF-induced phosphorylation of wild-type FGFR3 and downstream ERK phosphorylation in stable B9 cell transfectants (B9-WT) and FGFR3 expressing human myeloma cell lines. The antibody inhibited FGF-mediated growth of B9-WT with an IC50 of 3 μg/ml as determined by MTT proliferation assay. Growth of these cells could be rescued by IL-6 demonstrating selectivity of PRO-001 for FGFR3. PRO-001 inhibited the viability of the FGFR3 expressing, human myeloma cell line, UTMC2. Inhibition of viability was still observed when cells were co-cultured with stroma or in the presence of IL-6, a potent growth factor for MM cells. Several myeloma cell lines lacking FGFR3, showed minimal growth inhibition demonstrating selectivity and lack of non-specific toxic at effective dose concentrations. Finally, PRO-001 bound to FGFR3 on the cell surface, inhibited ERK phosphorylation, and induced cytotoxic responses in primary MM samples derived from t(4;14) positive patients. A xenograft mouse model has been established and studies assessing in vivo activity of PRO-001 are planned and will be reported. Taken together, the data demonstrate that PRO-001 is a specific and potent inhibitor of FGFR3 and that it deserves further study for targeted therapy in MM.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".