Fynomer Polypeptides Binding FGFR3 Isoforms
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Solution Overview
Problem
Current anti-FGFR3 antibodies have limitations such as recognizing only one isoform or displaying significant differences in affinity for different isoforms, necessitating molecules that can bind both FGFR3b and FGFR3c with high affinity and specificity, and be well internalized into cells.
Innovation Solution
Development of Fynomer polypeptides with specific amino acid sequences that bind to both FGFR3b and FGFR3c, exhibiting high affinity and internalization capabilities, including fusion constructs and pharmaceutical compositions for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional anti-FGFR3 antibodies are used, then binding to FGFR3 is achieved, but they recognize only one isoform or display significant differences in affinity for different isoforms
Solution Approach 1:
The patent develops Fynomer polypeptides that can bind to multiple FGFR3 isoforms (both FGFR3b and FGFR3c) with comparable high affinity, making the binding molecule universal across different isoform variants rather than specific to only one isoform
2Reliability
If high affinity binding to FGFR3 is achieved, then target specificity is improved, but internalization capability may be compromised
Solution Approach 1:
The patent optimizes specific amino acid residues in the Fynomer polypeptide sequence (such as residues in the RT loop and src loop regions) to achieve the right balance between maintaining high binding affinity and enabling efficient cellular internalization, demonstrating that parameter optimization can resolve the trade-off between these two properties
3Reliability
If conventional antibodies are used, then FGFR3 binding is achieved, but they lack optimal internalization properties for therapeutic efficacy
Solution Approach 1:
The patent systematically optimizes amino acid parameters in the Fynomer sequence, particularly in critical regions like the RT loop and src loop, to enhance internalization efficiency while preserving binding capability, thereby improving the overall therapeutic productivity of the molecule
Data Source
AI summary
The present invention relates to a polypeptide binding to fibroblast growth factor receptor 3 isoforms 3b and 3c (FGFR3b and FGFR3c), wherein the polypeptide comprises an amino acid sequence selected from the group consisting of: (a) GVTLFVALYDYEVYGPTPMLSFHKGEKFQIL(X1)(X2)(X3) (X4)GPYWEARSL(X5)TGETG(X6)IPSNYVAPVDSIQ (SEQ ID NO: 1), wherein amino acid positions (X1) to (X6) may be any amino acid sequence; (b) an amino acid sequence which is at least 95% identical to the amino acid sequence of (a), wherein the identity determination excludes amino acid positions (X1) to (X6) and provided that the amino acid sequence EVYGPTPM (SEQ ID NO: 2) in amino acid positions 12 to 19 of SEQ ID NO: 1 is conserved and the amino acids P and Y in amino acid positions 37 and 38 of SEQ ID NO: 1 are conserved; (c) GVTLFVALYDYEVMSTTALSFHKGEKF QILSQSPHGQYWEARSLTTGETG(X6)IPSNYVAPVDSIQ (SEQ ID NO: 19), wherein the amino acid position (X6) may be any amino acid; and (d) an amino acid sequence which is at least 95% identical to the amino acid sequence of (c), wherein the identity determination excludes amino acid position (X6) and provided that the amino acid sequences EVMSTTA (SEQ ID NO: 20) in amino acid positions 12 to 18 of SEQ ID NO: 19 and SQSPH (SEQ ID NO: 21) in amino acid positions 31 to 35 of SEQ ID NO: 19 are conserved and the amino acids Q and Yin amino acid positions 37 and 38 of SEQ ID NO: 19 are conserved.