Development of FGFR-based Bispecific ADCs

Bispecific antibody-drug conjugate (ADC) represents an attractive and novel therapy, which directly targets tumor-associated cell-surface antigens and provides targeted cytotoxic drug delivery with improved potency and reduced non-specific cytotoxic effects. With years’ experience in antibody discovery and ADC construction, Creative Biolabs now provides our worldwide clients with a comprehensive set of customized bispecific ADC development services to achieve your goals.

The Overview of FGFR

The human fibroblast growth factor receptor (FGFR) family consists of four members: FGFR1 to FGFR4. The four FGFR members share high homology, with their sequence identity varying from 56% to 71%. Similar to other receptor tyrosine kinases (RTKs), FGFRs are expressed on the cell membrane and can be stimulated and activated by extracellular signals. The native ligand of FGFRs is fibroblast growth factors (FGFs). The binding of FGFs drives the dimerization of FGFRs, subsequently, a transautophosphorylation event of the intracellular kinase domain is induced, followed by the activation of downstream transduction pathways. Through triggering downstream signaling pathways, FGFRs participate in various vital physiological processes, such as proliferation, differentiation, cell migration, and survival.

FGFRs share a canonical RTK architecture. From the N- to the C-terminus, all four FGFR members contain a large extracellular ligand-binding domain that comprises three immunoglobulin (Ig)-like subunits (D1, D2, and D3) followed by a single transmembrane helix and an intracellular tyrosine kinase domain.

The linker region between D1 and D2 contains a highly conserved motif that is rich in aspartate acids, called the acid box.
The FGF binding pocket is formed by the D2 and D3 subregions. The intracellular tyrosine kinase domain is the most well studied region of the FGFR protein. This domain exhibits the canonical bilobed architecture of protein kinases.
The fold of the N-terminal small lobe consists of a five-stranded antiparallel β-sheet and the αC-helix, an important regulatory element.
The C-terminal large lobe predominately comprises seven a helix. The active site, which is responsible for ATP and substrate protein binding, is located in a clef between the two lobes.

Fig.1 Schematic diagram of FGFRs and the structure of the FGFR domain. (Heidi, 2011)

Antibodies-based Therapeutics Targeting FGFRs

The ectodomains of FGFRs have attracted intensive interest in drug discovery. The dominant strategy to target FGFR ectodomains is using monoclonal antibody/antibody-drug conjugate. Several anti-FGFR monoclonal antibodies have been developed. Unlike the highly conserved kinase domain, the ectodomains of FGFRs are less conserved, antibody-targeting this domain may offer better selectivity. Phase I clinical trials involving several antibody-based drugs, including BAY1187982, FP-1039, MFGR1877S, and U3-1784, have been either completed or terminated. Of these agents, FP-1039 was reported to be well tolerated. Furthermore, trials involving bemarituzumab and B-701 have both provided preliminary data suggesting promising efficacy in patients with gastric cancers harboring FGFR2b overexpression and in those with urothelial carcinomas harboring FGFR3 alterations, but both agents currently remain in the early stages of clinical development.

What Can We Do for You?

Creative Biolabs is a leading ADC development company that serves the global market. With our unparalleled expertise in this field, we are dedicated to providing high quality bispecific ADC candidates for our clients all over the world. If you are interested in FGFR-based bispecific ADCs development services, please do not hesitate to inquire us for more details.

Reference