Anti-CD83 antibodies and use thereof
Inventors
Seldon, Therese Ann • Munster, David John • Hart, Derek Nigel John • Jones, Martina Louise • Munro, Trent Phillip • Mahler, Stephen Michael • Zhou, Yu • Marks, James D.
Assignees
Kira Biotech Pty Ltd • University of Queensland UQ • University of California San Diego UCSD
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Publication Number
US-10781255-B2
Publication Date
2020-09-22
Expiration Date
Abstract
The present disclosure relates to proteins that bind to CD83 and uses thereof, for example, in therapy, prophylaxis, diagnosis or prognosis.
Core Innovation
The invention relates to administering a CD83 binding protein to treat or prevent a CD83-associated disease or condition in a subject. The CD83 binding protein includes an antigen binding domain that specifically binds to CD83, and the antigen binding domain is defined by a heavy chain variable region (V_H) and a light chain variable region (V_L) using specified amino acid sequences and/or complementarity determining regions from listed SEQ ID NOs.
In particular, the heavy chain variable region comprises a sequence shown in SEQ ID NO: 1 or three complementarity determining regions of the amino acid sequence shown in SEQ ID NO: 1. The light chain variable region comprises any one of the amino acid sequences shown in SEQ ID NO: 5, 6, 7, 8, or 9, or three complementarity determining regions of any of those amino acid sequences, or a consensus sequence as shown in SEQ ID NO: 10, or three CDRs with CDR1, CDR2, or CDR3 amino acid sequences selected from consensus sequences shown in SEQ ID NO: 26, 27 or 28.
The described protein embodiments include antibody and antibody-like formats centered on a human mAb 3C12 derived from a phage-display human scFv library and reformatted to IgG1. Functional properties described include competitive binding versus polyclonal RA83, recognition of a conformational CD83 epitope, and CD16-dependent ADCC and lysis of CD83+ cells.
The disclosure further describes engineered enhancements to increase therapeutic potency, including light-chain affinity maturation by V_L shuffling to generate variants such as 3C12.B–E with improved binding, and glyco-engineering to generate afucosylated/low-fucose variants such as 3C12.Kif using kifunensine, including embodiments combining these changes. The engineered antibodies are described as increasing in vitro ADCC/MLR potency and supporting therapeutic use in CD83-associated settings.
Claims Coverage
The provided claim excerpt contains one independent claim directed to a treating or preventing method, with additional dependent claims refining structural and functional aspects. The inventive features center on a CD83-binding antigen binding domain defined by specified heavy- and light-chain variable regions and optionally refined by Fc properties, competitive inhibition, and specific indication scopes.
Cd83 binding protein defined by specified vh and vl sequences or cdr sets
A method comprising administering a CD83 binding protein comprising an antigen binding domain that specifically binds to CD83, wherein the CD83 binding protein comprises a heavy chain variable region (V_H) comprising a sequence shown in SEQ ID NO: 1 or three complementarity determining regions (CDRs) of the amino acid sequence shown in SEQ ID NO: 1, and a light chain variable region (V_L) comprising any one of the amino acid sequences shown in SEQ ID NO: 5, 6, 7, 8, or 9 or three CDRs of any one of the amino acid sequences shown in SEQ ID NO: 5, 6, 7, 8, or 9, or a consensus sequence as shown in SEQ ID NO: 10, or three CDRs wherein the amino acid sequence of CDR1, CDR2, or CDR3 is a consensus sequence shown in SEQ ID NO: 26, 27 or 28.
Fc region with enhanced effector function and/or extended half-life
A method where the CD83 binding protein comprises an Fc region that provides enhanced effector function and/or an extended half-life relative to a human IgG1 Fc region.
Competitive inhibition of a specifically defined cd83-binding antibody or epitope
A method where the CD83 binding protein competitively inhibits binding of an antibody defined by SEQ ID NO:29 and SEQ ID NO:30 to CD83, or binds to the same CD83 epitope as that antibody.
Therapeutic method for enumerated cd83-associated diseases and conditions
A method where the CD83-associated disease or condition is selected from allergy, asthma, graft or transplanted organ rejection, autoimmune conditions, chronic inflammatory bowel diseases, HLA B27-associated autoimmunopathis, skin diseases, rheumatoid arthritis, insulin-dependent diabetes mellitus, and AIDS.
Across the independent claim and its refinements shown, the coverage is directed to administering a CD83 binding protein for treating or preventing CD83-associated diseases, with the antigen binding domain defined by specified VH and VL variable region sequences or selected CDR sets from SEQ ID NOs. Further refinements shown include Fc-associated enhancement, competitive inhibition versus a specifically defined antibody/epitope, and an enumerated list of treatable disease or condition categories.
Stated Advantages
Improved survival in xenogeneic SCID mouse GVHD models with 3C12.
Increased in vitro ADCC/MLR potency for engineered variants compared to 3C12.WT and comparable potency to RA83 for 3C12.C.
Dose-dependent efficacy effects are described for 3C12 in vivo.
Documented Applications
Treating or preventing CD83-associated diseases or conditions, including allergy, asthma, graft or transplanted organ rejection, autoimmune conditions, chronic inflammatory bowel diseases, HLA B27-associated autoimmunopathis, skin diseases, rheumatoid arthritis, insulin-dependent diabetes mellitus, and AIDS.
Graft-versus-host disease (GVHD) modeling in xenogeneic SCID mice as described for 3C12 therapeutic evaluation.
Hematologic and immune-cell related in vitro functional contexts including ADCC and lysis of CD83+ cells, and MLR-based potency comparisons as described.
HSCT-related therapeutic/indication framing is described in the document summary.
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