Compositions
Inventors
Crowe, Scott • Roberts, Kevin • Carlton, Tim • Maggiore, Luana • Cubitt, Marion • West, Mike • Ray, Keith
Assignees
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Publication Number
US-11684677-B2
Publication Date
2023-06-27
Expiration Date
Abstract
There is provided inter alia a composition comprising a TNF-alpha binding polypeptide and an IL-6R binding polypeptide.
Core Innovation
The invention relates to compositions comprising a TNF-alpha-binding VHH and an IL-6R-binding VHH, where each VHH comprises three complementarity determining regions (CDR1-CDR3) with specified CDR sequences. The TNF-alpha-binding VHH comprises CDR1, CDR2, and CDR3 corresponding to SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the IL-6R-binding VHH comprises CDR1, CDR2, and CDR3 corresponding to SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11. The compositions are described for use in treating autoimmune and/or inflammatory diseases, including inflammatory bowel disease and mucositis.
The disclosed compositions combine TNF-alpha-binding and IL-6R-binding polypeptides in one composition and provide a rationale that additive and/or synergistic effects can be achieved by contacting both targets using the respective binding VHHs. The document discusses TNF-alpha neutralization and IL-6R neutralization in functional assays, and it further addresses trans-signalling and cis-signalling contexts associated with IL-6R biology. The compositions include structural and format variants described as VHH/ICVD formats and linked constructs.
The invention also addresses performance and stability in oral delivery-related contexts by specifying protease-labile and non-protease-labile peptide linkers and by describing retention of binding after exposure to intestinal protease matrices. Binding retention and survival are described using survival after exposure measures in mouse small intestinal supernatant and human faecal supernatant, and preliminary human oral delivery data are described with luminal concentrations at the ileal-caecal junction and in faeces after enteric-coated dosing. Ex vivo tissue experimentation is described to assess phosphorylation and cytokine modulation by TNF-alpha and IL-6R binding polypeptides alone and in combination.
Claims Coverage
The independent claim requires a composition comprising two specified VHHs: a TNF-alpha-binding VHH with defined CDR1-CDR3 sequences and an IL-6R-binding VHH with defined CDR1-CDR3 sequences, yielding coverage of a combined dual-binding composition as the core inventive concept.
Dual-target VHH composition with specified TNF-alpha and IL-6R CDR sequences
A composition comprising a TNF-alpha-binding VHH with CDR1 comprising SEQ ID NO: 1, CDR2 comprising SEQ ID NO: 2, and CDR3 comprising SEQ ID NO: 3, and an IL-6R-binding VHH with CDR1 comprising SEQ ID NO: 9, CDR2 comprising SEQ ID NO: 10, and CDR3 comprising SEQ ID NO: 11.
Binding affinity constraints for both VHHs
The composition wherein the TNF-alpha-binding VHH and the IL-6R-binding VHH have binding affinities characterized by Kd values of 10^-7 M or less.
Assay-based neutralization potency constraints
The composition wherein the TNF-alpha-binding VHH neutralizes human TNF-alpha cytotoxicity in an L929 assay and the IL-6R-binding VHH neutralizes IL-6R in a gp130 ELISA assay, each with an EC50 of 1 nM or less.
Protease-labile peptide linker connecting VHHs
The composition wherein a TNF-alpha-binding VHH and an IL-6R-binding VHH are connected by a protease-labile peptide linker.
Retention of binding after incubation in human faecal supernatant
The composition that maintains binding to TNF-alpha and IL-6R after 16 hours of incubation in human faecal supernatant.
Therapeutic targeting to inflammatory bowel disease and/or mucositis
The method wherein the autoimmune disease and/or inflammatory disease includes inflammatory bowel disease and/or mucositis.
The claims define a dual-specificity VHH composition with quantitative Kd and EC50 constraints, a protease-labile peptide linker, maintained binding after incubation in human faecal supernatant, and use embodiments that include inflammatory bowel disease and/or mucositis.
Stated Advantages
Demonstrated neutralization potency against TNF-alpha and IL-6R in specified assays with EC50 constraints stated in the claims.
Demonstrated binding affinity constraints for both VHHs (Kd ≤ 10^-7 M) as a claimed feature.
Improved gastrointestinal protease-relevant performance, expressed as retention of binding after incubation in human faecal supernatant.
Combined suppression effectiveness is described in the partial content for ex vivo IBD tissue with enhanced suppression with combined administration.
Documented Applications
Treatment of autoimmune disease and/or inflammatory disease, including inflammatory bowel disease (Crohn's disease, ulcerative colitis), Crohn’s disease, and mucositis.
Oral delivery using an enterically-coated pharmaceutical composition, with described detection at the ileal-caecal junction and detection in feces.
Ex vivo IBD tissue testing is described for TNF and IL-6R pathway effects and enhanced suppression with combined administration.
DSS colitis mice are mentioned in the partial content as disease models used to document functional outcomes.
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