Several Fibroblast Growth Factor Receptor 4 (FGFR4) specific antibodies with binding affinity at the nanomolar range have been successfully developed at the Genetics Branch. These antibodies have been made into different formats of therapeutic including Antibody Drug Conjugate (ADC), Bispecific T cell engager (BiTE) ae well as Chimeric Antigen Receptor (CAR)-T cells.
Proof of principle experiments have shown that when treated with FGFR4 positive tumor cells:
- FGFR4 specific antibodies were able to deliver cytotoxic agents and killed those cells.
- CD3 FGFR4 BiTE were able to recruit T cells to kill those cells.
- FGFR4 CAR-T cell was activated by cancer cells overexpressed FGFR4 and FGFR4 CAR-T cells were able to eliminate target cells both in vitro and in vivo
These findings are important in Rhabdomyosarcoma (RMS) as researchers at NCI's Genetics Branch found that high FGFR4 is overexpressed in RMS tumors compared with other normal tissue. RMS patients with higher FGFR4 expression is often associated with advanced disease, rapid disease progression, and poor survival. The correlation between FGFR4 expression and highly aggressive RMS makes the protein an attractive target for treatment.
RMS is a rare, yet the most common, soft tissue sarcoma in children and adolescents. Although current treatments for primary disease are relatively successful, metastatic RMS is generally accompanied by a dismal prognosis. Thus, these FGFR4 antibody- based therapeutics may fulfill the unmet medical needs for this disease. Moreover, over expression of FGFR4 has also been reported in other common malignancies including liver, lung, pancreas, ovary and prostate cancers. Therefore, FGFR4 specific therapeutics can also be used for treatment of these diseases.
- High affinity and specificity of the antibodies allows more selective targeting of cancer cells, reducing the potential for side effects during therapy
- Multiple antibodies available
- Potential to address significant unmet medical need
- Development of unconjugated antibody therapeutics
- Development of antibody-drug conjugates (ADCs) and recombinant immunotoxins
- Development of chimeric antigen receptors (CARs) and T cell receptors
- Development of bispecific antibody therapeutics
- Development of diagnostic agents for detecting FGFR4-positive cancers