Polypeptides which bind to interleukin-6 receptor (IL-6R)
Inventors
Crowe, Scott • Carlton, Tim • Cubitt, Marion • Roberts, Kevin • Maggiore, Luana • West, Mike • Ray, Keith
Assignees
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Publication Number
US-11401327-B2
Publication Date
2022-08-02
Expiration Date
Abstract
There is provided inter alia a polypeptide comprising an immunoglobulin chain variable domain which binds to IL-6R, wherein the immunoglobulin chain variable domain comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1-CDR3 and FR1-FR4 are as defined in the specification.
Core Innovation
The invention relates to interleukin-6 receptor (IL-6R)-binding immunoglobulin chain variable domain (ICVD) polypeptides. The ICVD comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), and binding to IL-6R inhibits IL-6R signaling via cis-signaling and/or trans-signaling through gp130.
The described ICVD polypeptides include CDR1 comprising SEQ ID NO: 1, CDR2 comprising SEQ ID NO: 2, and CDR3 comprising SEQ ID NO: 3. Additional structural definitions use Kabat numbering, including amino-acid selections associated with binding characteristics such as V33, G52, G56, and Y93, and optionally T18, T21, and F62.
A further aspect addresses suitability for oral delivery by emphasizing stability against gastrointestinal proteases and retention of activity following exposure to intestinal protease conditions. The document also describes enterically coated pharmaceutical composition formats and multivalent/bispecific bihead constructs with linkers described as protease-labile and/or non-protease-labile.
Claims Coverage
The document provides coverage through two independent claims. Across these claims, the polypeptides are defined by a specific ICVD architecture that binds IL-6R, with sequence-defined CDRs (SEQ ID NOs 1-3), FR1-FR4 framework regions, and further optional amino-acid position selections according to Kabat numbering.
IL-6R-binding immunoglobulin chain variable domain with defined CDR sequences
A polypeptide comprising an immunoglobulin chain variable domain that binds to IL-6R, wherein the immunoglobulin chain variable domain comprises three CDRs (CDR1-CDR3) and four framework regions (FR1-FR4), and wherein the polypeptide comprises a CDR1 comprising SEQ ID NO: 1, a CDR2 comprising SEQ ID NO: 2, and a CDR3 comprising SEQ ID NO: 3.
Kabat-position amino-acid selections in an IL-6R-binding ICVD
A polypeptide comprising an immunoglobulin chain variable domain that binds to IL-6R, wherein the immunoglobulin chain variable domain comprises three CDRs (CDR1-CDR3) and four framework regions (FR1-FR4), and wherein the polypeptide comprises a CDR1 comprising SEQ ID NO: 1, a CDR2 comprising SEQ ID NO: 2, and a CDR3 comprising SEQ ID NO: 3; wherein the immunoglobulin chain variable domain comprises one or more amino acids selected from V33, G52, G56 and Y93 and optionally one or more amino acids selected from T18, T21 and F62 according to Kabat numbering.
Overall, the claim coverage is directed to IL-6R-binding ICVD polypeptides defined by a specified CDR1-CDR3 sequence set (SEQ ID NOs 1-3) within an ICVD framework (FR1-FR4). One independent claim further limits additional amino-acid positions according to Kabat numbering (V33, G52, G56, Y93, and optional T18, T21, F62).
Stated Advantages
Increased affinity/specificity/neutralization of IL-6R signaling as described in the document.
Reduced immunogenicity as stated in the document.
Improved GI protease stability and retention of potency after exposure to human fecal extract.
Oral suitability via stability and enterically coated pharmaceutical composition.
Trans-selective inhibition as stated in the document.
Binding to additional/novel epitopes as stated in the document.
Documented Applications
Therapeutic use for autoimmune/inflammatory diseases including inflammatory bowel disease (IBD), specifically Crohn’s disease and ulcerative colitis.
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