Methods of administering a composition comprising a Tn3 scaffold and a CD40L-specific monomer
Inventors
Coyle, Anthony • BACA, MANUEL • Thisted, Thomas • Drabic, Stacey • Grinberg, Luba • Novarra, Shabazz • Oganesyan, Vaheh • Herbst, Ronald • Spencer, David Kenneth
Assignees
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Publication Number
US-11555062-B2
Publication Date
2023-01-17
Expiration Date
Abstract
The present invention provides Tenascin-3 FnIII domain-based scaffolds that specifically bind to CD40L. The invention further provides engineered variants with increased affinity for the target. The present invention is also related to engineered scaffolds as prophylactic, diagnostic, or therapeutic agents, in particular for therapeutic uses against SLE and other autoimmune diseases and conditions.
Core Innovation
The invention relates to Tn3 scaffold architectures comprising at least one CD40L-specific monomer subunit. The monomer subunit is defined by seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, with specified SEQ ID NO mappings for the loop regions. The scaffold is used in compositions that specifically bind CD40L.
The scaffold architecture includes tandem linkage, covalent/tandem linkage via peptide linkers, and multimeric formats that produce valency and avidity effects. The document also describes heterologous fusions and conjugates, including Tn3-HSA and Tn3-MSA fusions, as well as optional functional moieties such as purification tags, PEG, radionuclides/imaging agents, biotin, and albumin/HSA/Fc related components.
The disclosure further describes lead optimization, loop swapping among monomer variants, affinity maturation, and library screening/selection. It reports that BC and DE loops are critical for CD40L binding, and includes crystallization of CD40L complexes with selected Tn3 monomers and contact residues used for epitope mapping to support design of higher-affinity and tandem constructs.
Claims Coverage
Two independent claims are identified. Both claims cover administering an effective amount of a composition comprising a Tn3 scaffold with at least one CD40L-specific monomer subunit defined by seven beta strands and six loop regions with specified SEQ ID NO mappings; one claim is directed to autoimmune disease and the other to a disorder comprising inflammation.
CD40L-specific Tn3 scaffold with defined beta strands and loop regions
A Tn3 scaffold comprising at least one CD40L-specific monomer subunit defined by seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, with specified SEQ ID NO mappings for the loop regions.
Administering a CD40L-specific Tn3 scaffold for autoimmune disease
Administering an effective amount of a composition comprising a Tn3 scaffold to a subject with an autoimmune disease, where the Tn3 scaffold comprises at least one CD40L-specific monomer subunit with the specified beta strands and loop regions.
Administering a CD40L-specific Tn3 scaffold for a disorder comprising inflammation
Administering an effective amount of a composition comprising a Tn3 scaffold to a subject with a disorder comprising inflammation, where the Tn3 scaffold comprises at least one CD40L-specific monomer subunit with the specified beta strands and loop regions.
Across the independent claims, the core coverage is administration of an effective amount of a Tn3 scaffold composition defined by a CD40L-specific monomer subunit with seven beta strands and six loop regions, with fixed and selected SEQ ID NO assignments for the loops. The claims further distinguish autoimmune disease and disorders comprising inflammation.
Stated Advantages
Provides scaffold antibody mimetics that can specifically bind CD40L.
Can be engineered for increased affinity and stability.
Prevents CD40L binding to CD40 and provides associated functional antagonism.
Produces valency and avidity effects through tandem linkage of monomer subunits.
Improves CD40L binding, including reported potency gains.
Improves thermostability and monodispersity.
Supports serum half-life extension through FcRn binding when Fc/immunoglobulin domain components are used.
Documented Applications
Therapeutic/prophylactic/diagnostic use for autoimmune and inflammatory diseases, with emphasis on systemic lupus erythematosus (SLE).
Treating a disorder comprising inflammation, with further narrowing to cancer in dependent claims.
Treating a disorder selected from the group including asthma, encephalitis, inflammatory bowel disease, COPD, allergy, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, inflammatory osteolysis, viral infection, and bacterial infection.
Treatment or administration to a subject with an autoimmune disease using a composition comprising a Tn3 scaffold.
Treatment or administration to a subject with a disorder comprising inflammation using a composition comprising a Tn3 scaffold.
Cancer treatment as an inflammation-associated disorder option.
Asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), allergy, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, inflammatory osteolysis, viral infection, and bacterial infection.
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