Methods of treating FGF21-associated disorders

Inventors

Boettcher, Brian • CAPLAN, Shari Lynn • CEBE, Regis • Li, Guochun • Taraszka, John A. • Xu, Fangmin • Yowe, David Langdon

Assignees

Novartis AG • Novartis Pharma AG

Abstract

The present invention relates to monoclonal antibodies and antigen-binding fragments thereof that bind to human β-klotho, and pharmaceutical compositions and methods of treatment comprising the same.

Core Innovation

The invention relates to nucleic acids encoding an isolated antibody or antigen-binding fragment thereof that specifically binds to a human b2-klotho sequence (SEQ ID NO: 262). The antibody or antigen-binding fragment is defined by particular variable region compositions, including heavy chain variable regions comprising three heavy chain CDRs and light chain variable regions comprising three light chain CDRs, with multiple alternative CDR sets.

The disclosed variable region designs include heavy chain CDRs comprising SEQ ID NOS: 23, 24, and 25 with light chain CDRs comprising SEQ ID NOS: 33, 34, and 35; SEQ ID NOS: 26, 27, and 28 with SEQ ID NOS: 36, 37, and 38; SEQ ID NOS: 268, 24, and 25 with SEQ ID NOS: 33, 34, and 35; and SEQ ID NOS: 269, 270, and 271 with SEQ ID NOS: 272, 273, and 35. The disclosure further includes engineered and variant b2-klotho-binding antibodies covering conservative CDR modifications, framework changes, and identity-related constraints for VH/VL sequences relative to named SEQ ID NO amino acid sequences.

The document context further states FGF21 mimetic antibodies that bind human b2-klotho and activate the b2-klothoadFGFR1c receptor complex, supporting FGF21-mediated signaling. It also describes epitope characterization using HDx/HDx-MS with protected b2-klotho extracellular peptides/residues correlated with functional activity of the b2-klotho/FGFR1c signaling complex, including FGF21 activity, and includes antibody formats such as bispecific and multivalent molecules, including camelid nanobodies (VHH).

The disclosure further addresses reduced antigenicity and extended half-life strategies, in conjunction with variable-region definition by specified CDR sets. Antibody production is supported by constructs and nucleic acids, including production by culturing a host cell and isolating and/or purifying the produced antibody from culture medium. Overall, the innovation provides defined nucleic acid and antibody or antigen-binding-fragment specifications for binding b2-klotho (SEQ ID NO: 262) with epitope- and function-relevant variant coverage.

Claims Coverage

The independent claim is directed to nucleic acids coding for isolated antibodies or antigen-binding fragments that specifically bind b2-klotho sequence (SEQ ID NO: 262), with variable regions defined by sets of heavy-chain and light-chain CDRs. The inventive features are implemented through multiple alternative VH/VL CDR combinations and further refined by dependent claims that add sequence identity constraints and production-related components.

Across the independent claim and its dependents, the claim coverage is centered on nucleic acids encoding b2-klotho-specific antibodies or antigen-binding fragments defined by alternative heavy-chain and light-chain CDR sets, with further narrowing by VH/VL identity thresholds, specified heavy- and light-chain SEQ ID NO amino-acid sequences, and additional dependent claim elements directed to vectors, host cells, and production involving culturing followed by isolating and/or purifying from culture medium.

Stated Advantages

Documented Applications