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EP-4739346-A1 - COMBINATION THERAPIES FOR THE TREATMENT OF CANCER

EP4739346A1EP 4739346 A1EP4739346 A1EP 4739346A1EP-4739346-A1

Abstract

Provided is combination therapies that involve a construct has a TIGIT-binding moiety and a PVRIG-binding moiety and a KRAS G12C inhibitor for treating cancer with KRAS G12C mutations. In some cases, the construct is a multispecific antibody or a bispecific antibody that recognizes PVRIG and TIGIT.

Inventors

  • CHEN, ZHIJIAN
  • ZHANG, JING
  • RUI, Haopeng
  • WANG, Tienan
  • YANG, XIAOFENG

Assignees

  • D3 Bio(Wuxi) Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. A method of treating cancer in an individual, comprising administering to the individual an effective amount of 1) a construct comprising a TIGIT-binding moiety and a PVRIG-binding moiety; and 2) KRAS G12C inhibitor.
  2. The method of claim 1, wherein the construct comprises a multispecific antibody comprising a TIGIT antibody moiety and a PVRIG antibody moiety, optionally wherein the construct comprises a bispecific antibody.
  3. The method of claim 1 or claim 2, wherein the TIGIT-binding moiety blocks the binding of TIGIT and CD155, and wherein the PVRIG-binding moiety blocks the binding of PVRIG and PVRL2.
  4. The method of any one of claims 1-3, wherein the TIGIT is a human TIGIT.
  5. The method of any one of claims 1-4, wherein the PVRIG is a human PVRIG.
  6. The method of any one of claims 1-5, wherein the TIGIT-binding moiety and PVRIG-binding moiety are in any of a Fab and a scFv format.
  7. The method of claim 6, wherein, the TIGIT-binding moiety is in Fab format and the PVRIG-binding moiety is in scFv format; the TIGIT-binding moiety is in scFv format and the PVRIG-binding moiety is in Fab format; or both the TIGIT-binding moiety and the PVRIG-binding moiety are in Fab format.
  8. The method of any one of claims 1-7, wherein the construct further comprises an immunoglobulin constant region, such as an IgG constant region, such as a human IgG1, IgG4, IgG2, IgG3 Fc region or a variant thereof.
  9. The method of claim 8, wherein the human IgG Fc region is a human IgG1 Fc region or a variant thereof.
  10. The method of claim 8 or claim 9, wherein the variant comprises one or more substitutions to modulate receptor binding or effector function, to promote dimerization, to prevent glycosylation, and/or to extend its half-life.
  11. The method of any one of claims 1-10, wherein the construct comprises: (a) the TIGIT-binding moiety operably linked to the Fc region and the Fc region operably linked to the PVRIG-binding moiety; (b) the TIGIT-binding moiety operably linked to the PVRIG-binding moiety and the PVRIG-binding moiety operably linked to the Fc region; or (c) the PVRIG-binding moiety operably linked to the TIGIT-binding moiety and the TIGIT-binding moiety operably linked to the Fc region.
  12. The method of any one of claims 1-11, wherein the construct comprises one, two or more TIGIT-binding moieties, as well as one, two or more PVRIG-binding moieties.
  13. The method of any one of claims 1-12, wherein the construct comprises TIGIT-binding moieties that are identical or different, and/or the PVRIG-binding moieties that are identical or different.
  14. The method of any one of claims 1-13, wherein the construct comprises a full-length TIGIT antibody comprising two heavy chains and two light chains, and an anti-PVRIG scFv, wherein the anti-PVRIG scFv is fused to the N-or C-terminus of the two heavy chains of the full-length TIGIT antibody, optionally wherein the anti-PVRIG scFv is fused to the N-or C-terminus of the two heavy chains of the full-length TIGIT antibody via a linker, optionally wherein the linker is a peptide linker, optionally wherein the linker is a GS linker.
  15. The method of any one of claims 1-13, wherein the construct comprises a full-length PVRIG antibody comprising two heavy chains and two light chains, and an anti-TIGIT scFv, wherein the anti-TIGIT scFv is fused to the N-or C-terminus of the two heavy chains of the full-length PVRIG antibody, optionally wherein the anti-TIGIT scFv is fused to the N-or C-terminus of the two heavy chains of the full-length PVRIG antibody via a linker, optionally wherein the linker is a peptide linker, optionally wherein the linker is a GS linker.
  16. The method of any one of claim 1-15, wherein the TIGIT-binding moiety comprises an antibody moiety comprising a heavy chain variable region (VH) comprising a heavy chain CDR (HCDR) 1, a HCDR2, and a HCDR3, and a light chain variable region (VL) comprising a light chain CDR (LCDR) 1, a LCDR2 and a LCDR3, wherein: the HCDR1 comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 1, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 2, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 3, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 4, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 5, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 6, optionally wherein the substitution is a conservative substitution.
  17. The method of claim 16, wherein: the HCDR1 comprises the amino acid sequence of SEQ ID NO: 1, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 2, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 3, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 4, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 5, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 6.
  18. The method of any one of claims 1-17, wherein the PVRIG-binding moiety comprises an antibody moiety comprising a VH comprising a HCDR1, a HCDR2, and a HCDR3, and a VL comprising a LCDR1, a LCDR2 and a LCDR3, wherein: the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 7, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 8, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 9, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 10, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 11, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 12, optionally wherein the substitution is a conserved substitution.
  19. The method of claim 18, wherein: the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 8, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 9, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 10, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 11, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 12.
  20. The method of any one of claims 1-19, wherein the VH of the TIGIT-binding moiety comprises the amino acid sequence of SEQ ID NO: 13 or an amino acid sequence at least 85%, 90%, or 95%identical to SEQ ID NO: 13, and/or the VL of the TIGIT-binding moiety comprises the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence at least 85%, 90%, or 95%identical to SEQ ID NO: 14.

Description

COMBINATION THERAPIES FOR THE TREATMENT OF CANCER This application claims the benefit of PCT Application No. PCT/CN2023/106333, filed July 07, 2023, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION The present application relates to combination therapies for treating cancers with a construct comprising a TIGIT-binding moiety and a PVRIG-binding moiety; and a KRAS G12C inhibitor. BACKGROUND OF THE INVENTION The tumor immune microenvironment is a critical component of a patient’s response to immunotherapy. The same treatment can elicit varied responses, from minimal to no clinical benefit to pronounced clinical response. One factor in therapeutic response is T cell exhaustion. In the tumor microenvironment, persisting antigenic stimulation can result in T cell exhaustion, a state of T cell dysfunction, and high expression of co-inhibitory receptors including PD-1, LAG-3, TIM3, and TIGIT. TIGIT (T cell immune receptor with Ig and ITIM domains) , also known as Vstm3 and WUCAM, is a co-inhibitory receptor that is expressed on NK and CD8+ T cells, as well as a subset CD4+ T cells including immunosuppressive regulatory T cells (Tregs) [1-4] . There are four known ligands of TIGIT, poliovirus receptor (PVR) , PVRL2, PVRL3 and PVRL4, all of which are over-expressed by tumors and antigen-presenting cells, resulting in immune suppression [3, 5-8] . These ligands also bind the co-stimulatory molecule CD226 and the co-inhibitory molecule PVRIG and CD96 (the latter of which is sometimes considered co-stimulator) . Antagonistic antibodies of TIGIT disrupt binding of TIGIT to its ligands and block its inhibitory signals, shifting the balance in favor of CD226-mediated activating signals, which induces a strong anti-tumor immune response [9-11] . TIGIT is upregulated and identified as an exhaustion marker in cancer and inflammatory diseases [12-14] as other exhaustion markers like PD-1, LAG3 and TIM3 [15, 16] . Moreover, TIGIT is identified as a key inhibitory receptor of a new population of T cells, stem-like memory T cells, that may be the preferred targets for anti-PD- (L) 1 efficacy [17, 18] . Poliovirus receptor-related Ig domain containing (PVRIG, a. k. a. CD112R) is one of the co-inhibitory immune-checkpoint proteins. It plays an important role in reversion of T cell exhaustion and increasing NK cell activation [19-22] . PVRIG belongs to the nectin and nectin-like family, among which the family members also includes TIGIT, DNAM-1 (CD226) and CD96. PVRIG is expressed on NK and T cells and is further up-regulated in T cells upon activation [19, 20] . The interaction of PVRIG and its ligand PVRL2 (CD112) expressed on APC and multiple tumor cells results in suppression of T cell and NK cell activation [21, 22] . PVRL2 is also a ligand for CD226, which upon ligand interaction activates human T and NK cells [23-25] . Though PVRIG and TIGIT have many similarities, scientists have reported distinct differences that indicate the pathways are non-redundant [20, 22] . KRAS is a key regulator of cytokines that shape the tumor microenvironment. KRAS mutations play a role in many cancers. The KRAS G12C mutation, for example, accounts for about 44%of all KRAS mutations. G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12 of the KRAS protein that favors the active, GTP-bound conformation. This promotes constitutive activation of the signaling pathways that lead to oncogenesis. All references cited herein, including patent applications, patent publications, and UniProtKB/Swiss-Prot Accession numbers are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference. SUMMARY OF THE INVENTION The present application in one aspect provides a method of treating cancer in an individual, comprising administering to the individual 1) an effective amount of a construct comprising a TIGIT-binding moiety and a PVRIG-binding moiety; and 2) an effective amount of KRAS G12C inhibitor. In some embodiments, the TIGIT-binding moiety comprises an antibody moiety comprising a heavy chain variable region (VH) comprising a heavy chain CDR (HCDR) 1, a HCDR2, and a HCDR3, and a light chain variable region (VL) comprising a light chain CDR (LCDR) 1, a LCDR2 and a LCDR3, wherein: the HCDR1 comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 1, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 2 or  an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 2, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence with substitution of no more than 1, 2 or 3 amino acids compared with SEQ ID NO: 3, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence with substitution of no