Therapeutic variant alpha-2-macroglobulin compositions
Inventors
HANNA, Lewis • Laughlin, John David • BROWNING, Shawn Robert
Assignees
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Publication Number
US-11634475-B2
Publication Date
2023-04-25
Expiration Date
Abstract
A2M polypeptide compositions containing a non-natural bait region are disclosed. Methods of producing wild-type and variant A2M polypeptides and polynucleotides containing a non-natural bait region are also disclosed. The bait regions of the variant A2M polypeptides demonstrate enhanced protease inhibitory characteristics compared to wild-type A2M. Variant A2M polypeptides that demonstrate longer half-lives upon administration to an organism compared to wild-type A2M are disclosed. The A2M compositions are useful in treating a number of diseases and conditions including inflammation, chronic wounds, and diseases with a pathology associated with proteases.
Core Innovation
The disclosure relates to recombinant alpha-2-macroglobulin (A2M) polypeptides comprising a non-natural bait region. The non-natural bait region comprises a sequence comprising SEQ ID NO: 82 with specified X1 through X8 residue constraints and further comprises a sequence comprising EXE^4XG (SEQ ID NO: 83). The non-natural bait region comprises a sequence with at least 70% sequence identity to SEQ ID NO: 20 and does not comprise the listed excluded sequences.
The disclosure further relates to a pharmaceutical composition comprising a therapeutically effective amount of the recombinant A2M polypeptide and a pharmaceutically acceptable carrier. A related method of formulating the pharmaceutical composition is described by combining the recombinant A2M polypeptide with the pharmaceutically acceptable carrier. Dependent aspects state tighter sequence identity thresholds relative to SEQ ID NO: 20 and additional restrictions by selecting particular bait-region sequence variants.
The recombinant A2M variant bait regions are directed to improved protease inhibition compared with wild-type A2M. The bait regions are described as inhibiting fibronectin-aggrecan complex (FAC) formation, and the document context connects this with cartilage degradation and inflammation. The recombinant bait regions are also described as targeting proteases such as ADAMTS4/5 and multiple MMPs.
Claims Coverage
The independent claims include a composition claim and a method of formulating claim. Across these claims, the main inventive features are the recombinant A2M polypeptide with a non-natural bait region defined by SEQ ID NO: 82 residue constraints plus an EXE^4XG (SEQ ID NO: 83) motif, at least 70% sequence identity to SEQ ID NO: 20, exclusion of multiple specified SEQ IDs, and a pharmaceutically acceptable carrier.
Recombinant A2M polypeptide with non-natural bait region pattern (SEQ ID NO: 82)
A therapeutically effective amount of a recombinant alpha-2-macroglobulin (A2M) polypeptide comprising a non-natural bait region, where the non-natural bait region comprises a sequence comprising SEQ ID NO: 82 with residue constraints at X1–X8.
Additional EXE^4XG motif within the non-natural bait region (SEQ ID NO: 83)
The non-natural bait region further comprises a sequence comprising EXE^4XG (SEQ ID NO: 83).
Sequence identity to SEQ ID NO: 20 plus exclusion of specified bait-region sequences
The non-natural bait region comprises a sequence with at least 70% sequence identity to SEQ ID NO: 20, and the non-natural bait region does not comprise SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122 or SEQ ID NO: 123.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the recombinant A2M polypeptide with the defined non-natural bait region and a pharmaceutically acceptable carrier.
Formulating by combining recombinant A2M bait-region polypeptide with pharmaceutically acceptable carrier
A method of formulating a pharmaceutical composition by combining a therapeutically effective amount of the recombinant A2M polypeptide having the non-natural bait region defined by SEQ ID NO: 82 and EXE^4XG (SEQ ID NO: 83), meeting at least 70% sequence identity to SEQ ID NO: 20, and excluding the specified SEQ IDs, with a pharmaceutically acceptable carrier.
Across both independent claims, the central claimed concept is a recombinant A2M polypeptide whose non-natural bait region is defined by a SEQ ID NO: 82 pattern with specified residue constraints, includes EXE^4XG (SEQ ID NO: 83), has at least 70% sequence identity to SEQ ID NO: 20, and excludes multiple specified SEQ IDs, formulated as a pharmaceutical composition with a pharmaceutically acceptable carrier.
Stated Advantages
Improved protease inhibition versus wild-type A2M.
Inhibition of fibronectin-aggrecan complex (FAC) formation.
Documented Applications
Therapeutic use for inflammation and cartilage degradation and related joint/spine pain [procedural detail omitted for safety].
Therapeutic use for extracellular matrix degradation and chronic wounds [procedural detail omitted for safety].
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