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EP-4739708-A1 - IMPROVED FCRN ANTAGONISTS FOR TREATMENT OF IGG-RELATED DISEASES AND DISORDERS

EP4739708A1EP 4739708 A1EP4739708 A1EP 4739708A1EP-4739708-A1

Abstract

The present invention relates to FcRn antagonists which bind to the neonatal Fc receptor (FcRn) and interfere with binding of FcRn's natural ligands, the Fc region of IgG. In particular, the invention relates to FcRn antagonists comprising at least one first polypeptide specifically binding to an epitope on Fc receptor (FcRn) and a second polypeptide which competes with wild-type IgG1 Fc region for binding to FcRn. The invention also relates to fusion proteins comprising the FcRn antagonists, compositions comprising the FcRn antagonists and/or fusion proteins and the use of the FcRn antagonists, compositions comprising the FcRn antagonists and/or fusion proteins in medicine, in particular in the treatment of IgG-mediated disorders.

Inventors

  • VAN BOGAERT, Tom
  • VERHELST, Judith

Assignees

  • Ablynx N.V.
  • Sanofi

Dates

Publication Date
20260513
Application Date
20240705

Claims (18)

  1. CLAIMS 1. A FcRn antagonist comprising: a) At least one first polypeptide specifically binding to an epitope on Fc receptor (FcRn); and b) At least a second polypeptide which competes with wild-type IgG1 Fc region for binding to FcRn.
  2. 2. The FcRn antagonist according to claim 1, wherein the at least two polypeptides (a) and (b) comprised in the FcRn antagonist show a synergistic or cooperative effect, preferably wherein the synergistic or cooperative effect allows for an improved binding and/or a similar half-life of the FcRn antagonists, preferably an improved half-life of the FcRn antagonists, as compared with the binding and/or half-life of each of the at least two polypeptides (a) and (b) on their own.
  3. 3. The FcRn antagonist according to any one of claims 1 to 2, wherein the at least one first polypeptide as defined in (a) does not compete with wild-type IgG1 Fc region for binding to FcRn.
  4. 4. The FcRn antagonist according to any one of claims 1 to 3, wherein the at least one first polypeptide as defined in (a) comprises or consists of an immunoglobulin single variable domain (ISVD).
  5. 5. The FcRn antagonist according to claim 4, wherein the FcRn epitope to which the at least one ISVD binds comprises at least one of the following amino acid residues 1A, 2E, 3S, 4H, 5L, 32P, 97E, 98L, 99G, 100P, 101D, 102N, 103T, 164R, 167L, 168E, 171R, 174L, 175E, 177K, 204Y, 205P, 206P, 207E, 208L, 209Q, 255Q, 256H, 257A, 259L, 260A, 261Q, and/or 262P, amino acid residues being numbered according to SEQ ID NO: 1.
  6. 6. The FcRn antagonist according to claim 5, wherein the FcRn epitope to which the at least one ISVD binds comprises at least one of the following combinations of amino acid residues: a) 4H and 5L, and/or b) 98L, 99G, 100P, 101D and 102N, and/or c) 167L, 171R, 174L, 175E and 177K, and/or d) 255Q, 256H, 257A, 259L, 260A and 262P, amino acid residues being numbered according to SEQ ID NO: 1.
  7. 7. The FcRn antagonist according to any one of claims 1 to 6, wherein the at least one polypeptide as defined in (b) comprises or consists of a Fc domain or a fragment thereof.
  8. 8. The FcRn antagonist according to any one of claims 1 to 7, wherein the at least one polypeptide as defined in (b) specifically binds to FcRn with increased affinity relative to a wild-type IgG1 Fc region.
  9. 9. The FcRn antagonist according to any one of claims 7 to 8, wherein the Fc domain or fragment thereof comprises at least one, preferably all, of the following amino acids at the following positions: a) a tyrosine (Y) at amino acid position 252, b) a threonine (T) at amino acid position 254, c) a glutamic acid (E) at amino acid position 256, d) a lysine (K) at amino acid position 433, e) a phenylalanine (F) at amino acid position 434, and/or f) a tyrosine (Y) at amino acid position 436; according to EU numbering.
  10. 10. The FcRn antagonist according to any one of claims 7 to 8, wherein the Fc domain or fragment thereof comprises a combination of the following four amino acid residues: a) a tyrosine (Y) at amino acid position 252, b) an aspartic acid (D) or a glutamic acid (E) at amino acid position 256, c) a tryptophan (W) or a glutamine (Q) at amino acid position 307, and d) a phenylalanine (F) or a tyrosine (Y) at amino acid position 434; according to EU numbering.
  11. 11. The FcRn antagonist according to any one of claims 1 to 10, wherein the at least one first polypeptide as defined in (a) comprises or consists of SEQ ID NO: 14, 15, 185, 186, 131, 144,187, 158 or 168, preferably SEQ ID NO: 15 or 186.
  12. 12. The FcRn antagonist according to any one of claims 1 to 11, wherein the at least one second polypeptide as defined in (b) comprises or consists of SEQ ID NO: 22-24 and/or 119-123, preferably SEQ ID NO: 23, 24 or 119-123.
  13. 13. A fusion protein comprising the FcRn antagonists as defined in any one of claims 1 to 12 and a further group, residue, moiety or binding unit.
  14. 14. A composition comprising the FcRn antagonist as defined in any one of claims 1 to 12 and/or the fusion protein as defined in claim 13.
  15. 15. The FcRn antagonists as defined in any one of claims 1 to 12, the fusion protein as defined in claim 13 and/or the composition as defined in claim 14 for use in medicine, preferably for use in the treatment of an IgG-mediated disorder such as an autoimmune disease.
  16. 16. A nucleic acid or nucleic acid sequence encoding a FcRn antagonist as defined in any one of claims 1 to 12 and/or the fusion protein as defined in claim 13.
  17. 17. A vector comprising a nucleic acid or nucleic acid sequence as defined in claim 16.
  18. 18. A non-human host or a host cell comprising a vector comprising a nucleic acid sequence as defined in claim 17 or expressing a nucleic acid sequence as defined in claim 16.

Description

Improved FcRn antagonists for treatment of IgG-related diseases and disorders FIELD OF THE INVENTION The present invention relates to FcRn antagonists which bind to the neonatal Fc receptor (FcRn) and interfere with binding of FcRn’s natural ligands, the Fc region of IgG. In particular, the present invention relates to novel and improved FcRn antagonists comprising at least two polypeptides, a first polypeptide specifically binding to an epitope on FcRn and a second polypeptide which competes with wild-type IgG1 Fc region for binding to FcRn. The invention further relates to nucleic acids encoding such molecules or part of such molecules; to host cells comprising such nucleic acids and/or expressing or capable of expressing such FcRn antagonists; to compositions, and in particular to pharmaceutical compositions that comprise such FcRn antagonists, nucleic acids and/or host cells; and to uses of such molecules, nucleic acids, host cells and/or compositions, in particular for therapeutic purposes. TECHNOLOGICAL BACKGROUND The neonatal Fc receptor (FcRn) is a beta (β)-2-microglobulin (β2m) associated protein that is widely expressed with predominant expression on parenchymal, endothelial and hematopoietic cells. FcRn is predominantly localised intracellularly within vesicular networks, particularly endosomes. FcRn has two known ligands, IgG and albumin, which together account for almost 70% of total serum proteins. IgG and albumin bind to FcRn at distinct sites. Immunoglobulin gamma (IgG) antibodies are fundamental to the immune response. IgG has a prolonged serum half-life due to its interaction with FcRn, which protects it from intracellular degradation by a cellular recycling mechanism. FcRn binds to endocytosed IgG and protects the IgG from being transported to degradative lysosomes by recycling it back to the extracellular compartment. This recycling mechanism is strictly pH-dependent and binding to FcRn is favoured at low pH (e.g., acidic endosomal pH, which is typically below 6.5) following acidification of the endosomal compartment. When IgG binds to FcRn, it escapes degradation in the lysosome. On return to the cell surface, at extracellular physiological pH (which is typically around pH 7.4), the binding is weakened, resulting in the release of IgG into the bloodstream. Modulation of the FcRn/IgG interaction may be beneficial in therapy. It has been found that FcRn-mediated IgG recycling is the dominant process for maintaining IgG plasma concentrations in humans (Xiao, J Biomed Biotechnol. (2012) 2012:282989). For example, FcRn antagonists, which block the binding of IgG to FcRn, are being used to increase the clearance of IgG from the circulation. This may be desirable in diseases where IgG antibodies play a key role in the pathology, such as autoimmune diseases where circulating autoreactive antibodies cause the pathology, inflammatory diseases and diseases where the pathology is characterised by overexpression of IgG antibodies. Increased clearance of an undesired antibody can be achieved by using an FcRn antagonist, such as an antibody with an engineered Fc, that binds to FcRn with high affinity and does not dissociate rapidly at near neutral pH. Such engineered antibodies are called Abdegs, for antibodies that enhance IgG degradation (Swiercz et al, J Nucl Med. (2014) 55(7): 1204-7). Such FcRn antagonists would not be released from cells but would instead be predicted to remain bound to FcRn and block binding of other, lower affinity IgGs. As a result, FcRn function would be blocked and endogenous or undesired IgGs would be directed into the lysosomal pathway for degradation. Examples of antibodies to human FcRn which block or reduce the binding of IgG to FcRn have been described in, e.g., WO 2014/019727. WO 2019/118791 relates to antibodies that bind FcRn with high affinity. WO 2015/167293 relates to antibodies that competitively inhibit the binding of IgG to FcRn. Engineered Fc fragments that compete with and inhibit the binding of IgG have also been described, see, e.g., WO 2019/110823, WO 2015/100299 and WO 2021/016571. These Fc fragments have been shown to increase the rate of serum IgG clearance in the treated subject. These molecules have increased affinity and reduced pH dependence compared to IgG and therefore block FcRn. As a result, endogenous or unwanted IgG is directed to the lysosomal pathway for degradation. However, the duration of the efficacy of known FcRn antagonists is thought to be reduced because either the affinity for FcRn is low, resulting in incomplete and/or poor blocking, or - if the affinity is high enough to block FcRn sufficiently - the half-life of the FcRn antagonist is automatically reduced as a direct consequence of extensively blocking the recycling mechanism modulated by FcRn. For instance, FcRn antagonists that bind pH-independently, such as some anti-FcRn antibodies, efficiently block FcRn at neutral pH by ensuring that FcRn is already occupied at the c