Polynucleotides encoding, and method of making, a polypeptide comprising a VHH which binds interleukin-receptor (IL-7R)
Inventors
Crowe, Scott • West, Mike • Roberts, Kevin • Carlton, Tim • Maggiore, Luana • Cubitt, Marion • DUARTE, Lurdes • SYMMONS, Martyn • Ray, Keith
Assignees
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Publication Number
US-12247079-B2
Publication Date
2025-03-11
Expiration Date
Abstract
There are provided inter alia polypeptides capable of inhibiting IL-7 and/or L-TSLP binding to IL-7R (IL-7R), as well as to constructs and pharmaceutical compositions comprising these polypeptides.
Core Innovation
The invention relates to IL-7Rα-binding VHH and ICVD polypeptides that inhibit IL-7 and/or L-TSLP binding to IL-7Rα. The polypeptides include engineered variants and humanisation, including examples such as V7R-2E9 and engineered variants including ID-A62U and ID-A40U.
A key aspect of the invention is the definition of the VHH by complementarity determining regions CDR1, CDR2, and CDR3, including options set forth by specific SEQ ID NO assignments. The document further includes frameworks for sequence identity thresholds and engineered variants, and specifies epitope residues on IL-7Rα for at least one VHH example.
Constructs and multimer formats are described, including bihead and multivalent constructs. The document also describes functional binding and inhibition characteristics, including dual antagonism by blocking IL-7 and L-TSLP binding to IL-7Rα, cross-reactivity with human and cynomolgus monkey IL-7Rα, and protease stability in intestinal/digestive matrices and buccal/GI contexts.
Claims Coverage
The independent claim covers a polynucleotide encoding a VHH that binds IL-7R, where the VHH is defined by specified CDR1, CDR2, and CDR3 amino acid sequences using SEQ ID NOs. Two inventive feature sets are identified, both centered on the defined VHH CDR sequence sets and functional binding specificity toward IL-7R. Downstream dependent claims further refine sequence identity options and inhibition of IL-7 and/or L-TSLP binding, and define aspects of production and host cell expression frameworks.
VHH binding to IL-7R defined by SEQ ID CDR1/CDR2/CDR3 set
A polynucleotide encoding a VHH wherein the VHH comprises CDR1, CDR2, and CDR3 amino acid sequences as set forth in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and wherein the VHH binds IL-7R.
VHH binding to IL-7R defined by alternative SEQ ID CDR set options
A polynucleotide encoding a VHH wherein the VHH comprises a CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 71, a CDR2 comprising an amino acid sequence of any one as set forth in SEQ ID NOs: 72, 73, 74, or 75, and a CDR3 comprising an amino acid sequence of any one as set forth in SEQ ID NOs: 77 or 78, and wherein the VHH binds IL-7R.
Overall claim coverage centers on a polynucleotide encoding a VHH that binds IL-7R, with the VHH defined by either specific SEQ ID NO: 1/2/3 CDR1/CDR2/CDR3 sequences or an alternative CDR1 set (SEQ ID NO: 71) with permitted alternative CDR2 and CDR3 SEQ ID options (SEQ ID NOs: 72/73/74/75 and 77/78).
Stated Advantages
High affinity/potency as assessed by ELISA/functional cell assays compared with mAb829 (GSK2618960).
Dual antagonism by blocking IL-7 and L-TSLP binding to IL-7Rα.
Cross-reactivity to human and cynomolgus monkey IL-7Rα.
Protease stability relevant to oral GI delivery, including survival in intestinal/digestive matrices and buccal/GI contexts.
Reduced immunogenicity due to humanisation.
Documented Applications
Treatment or use in inflammatory/autoimmune indication contexts, including IBD (Crohn’s disease, ulcerative colitis).
Eosinophilic esophagitis (EoE).
Oral delivery context associated with the intestinal tract/buccal-GI contexts for survival in digestive matrices.
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