Modified Fc proteins comprising site-specific non-natural amino acid residues, conjugates of the same, methods of their preparation and methods of their use
Inventors
Thanos, Christopher D. • McEvoy, Leslie • Yin, Gang • Penta, Kalyani • Baliga, Ramesh • BAJAD, Sunil • Pollitt, Sonia • Murray, Chris • Steiner, Alex • Gill, Avinash
Assignees
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Publication Number
US-12252552-B2
Publication Date
2025-03-18
Expiration Date
Abstract
Provided herein are modified Fc proteins comprising non-natural amino acid residues at site-specific positions, conjugates of the modified Fc proteins for therapy or diagnosis, compositions comprising the modified Fc proteins and conjugates thereof, methods of their production and methods of their use. The modified Fc proteins and conjugates are useful for methods of treatment and prevention, methods of detection and methods of diagnosis.
Core Innovation
The invention provides an Fc protein conjugate for treating cancer in a subject. The Fc protein comprises a polypeptide chain having one or more non-natural amino acid residues at specific sites selected from heavy chain residues H404, H241, and H222 according to the EU index of Kabat, including post-translationally modified variants or aglycosylated variants. Each non-natural amino acid is selected from ortho-substituted tyrosine, meta-substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine.
At least one of the non-natural amino acids is linked to one or more payloads selected from anti-tubulin agents, auristatins, maytansinoids, platinols, rapamycins, steroids, and topoisomerase inhibitors. The non-natural amino acids provide reactive groups that enable covalent linkage to payloads via linkers, including oxime/oxime-like groups via oxime exchange for attaching labels, drugs, cytotoxins, affinity/photoaffinity ligands, PEG derivatives, biomaterials, metal chelators, and other payload or functional moieties.
The disclosure also describes selective coupling chemistry for these residues, including azide/alkyne click and related reactive functionalities and carbonyl/aminooxy/hydrazide/semicarbazide-type groups. It also includes PEG-linker functionalization and heterobifunctional PEGs for conjugation, with coupling to Fc proteins via carbonyl-containing non-natural amino acids and adjustable conjugation level to modulate serum half-life.
Claims Coverage
The provided claim coverage centers on an Fc protein conjugate for cancer treatment with one or more non-natural amino acid residues at specified Kabat heavy-chain positions, defined non-natural amino acid identities, and linkage to specified payload classes. Three inventive features are present: site-specific Fc modification, restricted non-natural amino acid selection, and payload linkage.
Site-specific Fc conjugation at Kabat heavy-chain residues
An Fc protein conjugate for treating cancer in a subject comprising an Fc protein whose polypeptide chain has one or more non-natural amino acid residues at specific sites selected from heavy chain residues H404, H241, and H222 according to the EU index of Kabat, including a post-translationally modified variant or an aglycosylated variant.
Restricted non-natural amino acid selection at designated sites
Each non-natural amino acid is selected from ortho-substituted tyrosine, meta-substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine.
Payload linkage from non-natural amino acid residues
At least one of the non-natural amino acids is linked to one or more payloads selected from anti-tubulin agents, auristatins, maytansinoids, platinols, rapamycins, steroids, and topoisomerase inhibitors.
Overall, the claim coverage centers on an Fc protein conjugate with non-natural amino acid residues at Kabat heavy-chain positions H404, H241, and H222, selected from defined ortho/meta/para substituted tyrosine or phenylalanine classes, and linked to specified payload classes.
Stated Advantages
Stability and functional advantages are expected from the selected nnAA substitution sites.
Stability in mildly acidic aqueous conditions.
Adjustable conjugation level to modulate serum half-life.
Aqueous stability under mildly acidic pH conditions (pH 2 to 8) for weeks to months.
Documented Applications
Treating cancer in a subject by administering an Fc protein conjugate.
Conjugation of water-soluble polymers, including PEG, to Fc proteins.
Incorporation of the non-natural amino acids into non-natural amino-acid polypeptides, polymers, polysaccharides, and polynucleotides.
Use of the non-natural amino acids in constructs supporting optional post-translational modification.
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