Polypeptides comprising immunoglobulin chain variable domains which bind to interleukin-6 receptor (IL-6R) and methods of use thereof to treat autoimmune and inflammatory diseases
Inventors
Crowe, Scott • Carlton, Tim • Cubitt, Marion • Roberts, Kevin • Maggiore, Luana • West, Mike • Ray, Keith
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12098197-B2
Publication Date
2024-09-24
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 IL-6R-binding immunoglobulin chain variable domain polypeptides. Each immunoglobulin chain variable domain binds to IL-6R and comprises three complementarity determining regions (CDR1-CDR3), with CDR1, CDR2, and CDR3 defined by amino acid sequences set forth in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:50, respectively, using Kabat numbering along with framework regions FR1-FR4.
The document describes multivalent and multispecific antibody-like constructs, including heterobihead and homobihead concepts, and combination with optional non-IL-6R-binding polypeptides. It also describes antibody-fragment formats including VHH, VH, VL, V-NAR, Fab, and F(ab')2, together with direct or linker-mediated linkage and assembly strategies, including protease-labile and non-protease-labile linker formats.
The invention addresses IL-6 cis/trans signalling through membrane-bound IL-6R (mIL-6R), soluble IL-6R (sIL-6R), and gp130, and the need for therapeutic molecules that inhibit IL-6 mediated inflammatory responses. It is described as providing improved therapeutic properties for oral administration and gastrointestinal exposure, including intestinal protease resistance and stability, oral/local delivery, and intestinal lamina propria penetration after oral dosing.
The invention is described as therapeutically useful for autoimmune and inflammatory diseases, including inflammatory bowel disease such as Crohn’s disease and ulcerative colitis/IBD, skin inflammation, and mucositis. Combination-therapy and kit-of-parts concepts are included, and the document describes generation and selection of IL-6R-binding ICVDs from llama phage display libraries, together with cross-reactivity, epitope competition versus tocilizumab, and ex vivo IBD efficacy readouts for specific IL-6R-binding ICVDs and variants.
Claims Coverage
The independent claim is directed to an IL-6R-binding polypeptide defined by specific CDR1, CDR2, and CDR3 sequences taken from SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:50. The claim set also includes dependent features relating to alternative sequence identity, antibody and fragment formats, protease resistance, and enterically coated pharmaceutical composition form, resulting in six inventive feature groupings.
IL-6R-binding immunoglobulin chain variable domain with defined CDR1-CDR3 sequences
A polypeptide comprising an immunoglobulin chain variable domain that binds to IL-6R, wherein the immunoglobulin chain variable domain comprises three complementarity determining regions (CDR1-CDR3) wherein CDR1 comprises the amino acid sequence set forth in SEQ ID NO: 1, wherein CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2, and wherein CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 50.
Alternative immunoglobulin sequence identity
The polypeptide comprises the amino acid sequence specified as SEQ ID NO: 31.
Antibody format
The polypeptide is an antibody.
Specific variable-domain and fragment classes
The polypeptide is selected from the group consisting of a VHH, a VH, a VL, a V-NAR, a Fab fragment, and a F(ab')2 fragment.
Substantially protease-resistant polypeptide for gastrointestinal exposure
The polypeptide is substantially resistant to one or more proteases found in the stomach or small or large intestine.
Enterically coated pharmaceutical composition
The pharmaceutical composition is provided in an enterically coated form.
Overall, the claim set defines IL-6R-binding immunoglobulin chain variable domains by specific CDR sequence assignments and includes dependent coverage for an alternative sequence identity, antibody and fragment formats, multivalent and multispecific antibody-like construct concepts, gastrointestinal protease resistance, and an enterically coated pharmaceutical composition form.
Stated Advantages
Intestinal protease resistance and stability.
Oral delivery rationale.
Intestinal lamina propria penetration after oral dosing.
Increased affinity/specificity/potency.
Cross-reactivity including cynomolgus monkey.
Reduced immunogenicity.
Enhanced protease stability for small and large intestine exposure.
Improved oral/local delivery.
Preference for trans-signalling inhibition over cis-signalling inhibition.
Documented Applications
Therapeutic use for autoimmune and inflammatory diseases.
Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis/IBD.
Skin inflammation.
Treatment for mucositis.
Combination therapy and kit-of-parts concepts.
Interested in licensing this patent?