Search

EP-4735482-A1 - ANTI-HER2 ANTIBODY FOR USE IN TREATING A LOW HER2 EXPRESSING TUMOR IN A SUBJECT

EP4735482A1EP 4735482 A1EP4735482 A1EP 4735482A1EP-4735482-A1

Abstract

In one aspect, the present invention relates to an anti-HER2 immunoglobulin E (IgE) antibody for use in treating a low HER2-expressing tumor in a subject. In another aspect, immunoglobulins that bind to HER2 are provided.

Inventors

  • FITZGERALD, KEVIN
  • WILSON, TIM

Assignees

  • Epsilogen Ltd

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. CLAIMS 1. An anti-HER2 immunoglobulin E (IgE) antibody for use in treating a low HER2- expressing tumor in a subject.
  2. 2. An IgE antibody for use according to claim 1, wherein less than 10% of tumor cells in a sample from the subject show strong complete membrane staining for HER2 using immunohistochemical detection of HER2.
  3. 3. An IgE antibody for use according to claim 1 or claim 2, wherein using immunohistochemical detection of HER2, at least 10% of tumor cells or a tumor cell cluster (5 or more cells) in a sample from the subject show weak to moderate complete membrane staining for HER2.
  4. 4. An IgE antibody for use according to claim 1 or claim 2, wherein using immunohistochemical detection of HER2, at least 10% of tumor cells or a tumor cell cluster (5 or more cells) in a sample from the subject show faint or barely perceptible partial membrane staining for HER2.
  5. 5. An IgE antibody for use according to any preceding claim, wherein immunohistochemical detection of HER2 in a sample from the subject is performed using a Dako anti-HER2 immunohistochemistry system (HercepTest™); preferably wherein a tumor sample from the subject has a HER2 immunohistochemical staining (HER2 IHC) score of 2+ or lower, more preferably 2+ or 1+.
  6. 6. An IgE antibody for use according to any preceding claim, wherein the tumor has a HER2/CEN17 ratio < 2.0 or shows no detectable erbB2 gene amplification as determined by fluorescence in situ hybridization.
  7. 7. An IgE antibody for use according to any preceding claim, wherein tumor HER2 expression in the subject is lower than in at least 50% of cancer subjects; preferably wherein membrane HER2 expression in tumor cells of the subject is lower than in at least 60%, at least 70% or at least 80% of subjects suffering from the same form of cancer; more preferably wherein tumor HER2 expression in the subject is lower than in at least 50%, at least 70% or at least 90% of HER2-expressing tumors (preferably HER2-expressing breast tumors).
  8. 8. An IgE antibody for use according to any preceding claim, wherein the tumor expresses HER2; preferably wherein at least 1%, 5%, 10%, 15% or 20% of tumor cells in the subject show detectable membrane HER2 expression using immunohistochemical detection of HER2.
  9. 9. An IgE antibody for use according to any preceding claim, wherein the antibody binds to subdomain II of the extracellular domain of the HER2, preferably wherein the antibody at least partially competes with pertuzumab IgG for binding to HER2.
  10. 10. An IgE antibody for use according to any preceding claim, wherein the antibody binds to subdomain IV of the extracellular domain of the HER2, preferably wherein the antibody at least partially competes with trastuzumab IgG for binding to HER2.
  11. 11. An IgE antibody for use according to any preceding claim, wherein the antibody is trastuzumab IgE.
  12. 12. An IgE antibody for use according to any preceding claim, wherein the antibody comprises an amino acid sequence as defined in any one of SEQ ID NO:s 1 to 40.
  13. 13. An IgE antibody for use according to claim 12, wherein the antibody comprises one to six CDR sequences selected from: (i) SEQ ID NOs: 3, 4, 5, 8, 9 and 10; (ii) SEQ ID NOs: 13, 14, 15, 18, 19 and 20; (iii) SEQ ID NOs: 23, 24, 25, 28, 29 and 30; or (iv) SEQ ID NOs: 33, 34, 35, 38, 39 and 40.
  14. 14. An IgE antibody for use according to claim 12 or claim 13, wherein the antibody comprises: (i) a heavy chain variable domain sequence as defined in any one of SEQ ID NOs: 2, 12, 22 or 32; (ii) a light chain variable domain sequence as defined in any one of SEQ ID NOs: 7, 17, 27 or 37; (iii) a heavy chain sequence as defined in any one of SEQ ID NOs: 1, 11, 21 or 31; and/or (iv) a light chain sequence as defined in any one of SEQ ID NOs: 6, 16, 26 or 36.
  15. 15. An IgE antibody for use according to any preceding claim, for use in treating and/or delaying progression of cancer in the subject.
  16. 16. An IgE antibody for use according to any preceding claim, wherein the tumor or cancer is a breast tumor or breast cancer.
  17. 17. An IgE antibody for use according to any preceding claim, wherein the antibody lacks a cytotoxic moiety, preferably wherein the antibody is not an antibody-drug conjugate (ADC).
  18. 18. A method for treating and/or delaying progression of cancer in a subject having a low HER2-expressing tumor, the method comprising a step of administering an anti-HER2 immunoglobulin E (IgE) antibody as defined in any preceding claim to the subject in a therapeutically-effective amount.
  19. 19. A pharmaceutical composition for use in treating a low HER2-expressing tumor in a subject, comprising an anti-HER2 immunoglobulin E (IgE) antibody as defined in any of claims 1 to 17 and one or more pharmaceutically acceptable excipients, carriers or diluents.
  20. 20. An immunoglobulin, or a functional fragment thereof, comprising one to six CDR sequences selected from: (i) SEQ ID NOs: 13, 14, 15, 18, 19 and 20; (ii) SEQ ID NOs: 23, 24, 25, 28, 29 and 30; or (iii) SEQ ID NOs: 33, 34, 35, 38, 39 and 40. 21. An immunoglobulin or functional fragment thereof according to claim 20, wherein the immunoglobulin comprises: (i) a heavy chain variable domain sequence as defined in any one of SEQ ID NOs: 12, 22 or 32; (ii) a light chain variable domain sequence as defined in any one of SEQ ID NOs: 17, 27 or 37; (iii) a heavy chain sequence as defined in any one of SEQ ID NOs: 11,

Description

COMPOSITION FIELD OF THE INVENTION The present invention relates to the field of therapeutic antibodies and uses thereof and in particular to immunoglobulin E (IgE) antibodies for use in treating cancer. The present invention also relates to methods of treating diseases such as cancer using such IgE antibodies. BACKGROUND Therapeutic antibodies now complement conventional treatments for a number of malignant diseases, but almost all agents currently developed rely on only one of the nine human antibody classes, namely IgGı, the most abundant antibody class in the blood (Weiner LM, Surana R, Wang S (2010) Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10: 317-327). The human immune system naturally deploys nine antibody classes and subclasses (IgM, IgD, IgG1-4, IgAl , IgA2 and IgE) to perform immune surveillance and to mediate destruction of pathogens in different anatomical compartments. Yet only IgG (most often IgG1) has been applied in immunotherapy of cancers. One reason may be that IgG antibodies (particularly IgG1), constitute the largest fraction of circulating antibodies in human blood. The choice of antibody class is also based on pioneering work in the late 1980s, comparing a panel of chimaeric antibodies of the same specificity, each with Fc regions belonging to one of the nine antibody classes and subclasses (Bruggemann M, Williams GT, Bindon CI, Clark MR, Walker MR, Jefferis R, Waldmann H, Neuberger MS (1987) Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies. J Exp Med 166: 1351-1361). Antibodies were evaluated for their ability to bind complement and their potency to mediate haemolysis and cytotoxicity of antigen- expressing target cells in the presence of complement. IgG1 in combination with human peripheral blood mononuclear cells (PBMC) was the most effective IgG subclass in complement-dependent cell killing in vitro, while the IgA and IgE antibodies were completely inert. Subsequent clinical trials with antibodies recognising the B cell marker CD20 supported the inference that IgG1 would be the subclass best suited for immunotherapy of patients with B cell malignancies such as non-Hodgkin’s lymphoma (Alduaij W, Illidge TM (2011) The future of anti-CD20 monoclonal antibodies: are we making progress? Blood 117: 2993-3001). Since those studies, comparisons of anti-tumour effects by different antibody classes have been confined to IgG and IgM in both murine models and patients with lymphoid malignancies, while IgA has been shown to mediate ADCC in vitro and in vivo in mouse models of lymphoma (Dechant M, Valerius T (2001) IgA antibodies for cancer therapy. Crit Rev Oncol Hematol 39: 69-77). The HER family of receptor tyrosine kinases are important mediators of cell growth, differentiation and survival. The receptor family includes four distinct members including epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2 or pl85neu), HER3 (ErbB3) and HER4 (ErbB4 or tyro2). EGFR, encoded by the erbB1 gene, has been causally implicated in human malignancy. In particular, increased expression of EGFR has been observed in breast, bladder, lung, head, neck and stomach cancer as well as glioblastomas. Increased EGFR receptor expression is often associated with increased production of the EGFR ligand, transforming growth factor alpha (TGF-α), by the same tumor cells resulting in receptor activation by an autocrine stimulatory pathway (Baselga and Mendelsohn, Pharmac. Ther. 64:127-154 (1994)). Monoclonal antibodies directed against the EGFR or its ligands, TGF-α and EGF have been evaluated as therapeutic agents in the treatment of such malignancies (see e.g., Baselga and Mendelsohn., supra; Masui et al. Cancer Research 44:1002-1007 (1984); and Wu et al. J. Clin. Invest. 95:1897-1905 (1995)). The second member of the HER family, i.e. HER2, was originally identified as the product of the transforming gene from neuroblastomas of chemically treated rats. The activated form of the neu proto-oncogene results from a point mutation (valine to glutamic acid) in the transmembrane region of the encoded protein. Amplification of the human homolog of neu is observed in breast and ovarian cancers and correlates with a poor prognosis (Slamon et al. , Science, 235: 177-182 (1987); Slamon et al. , Science, 244:707-712 (1989); and US Pat No. 4,968,603). Overexpression of HER2 (frequently but not uniformly due to gene amplification) has also been observed in other carcinomas including carcinomas of the stomach, endometrium, salivary gland, lung, kidney, colon, thyroid, pancreas and bladder (see e.g. Ross et al Cancer 79:2162-70 (1997); and Sadasivan et al J. Urol.150:126-31 (1993)). IgG antibodies directed against human HER2 protein products have been described. See, for example, Drebin et al, Cell 41:695-706 (1985) and U.S. Patent 5,824,311. Hudziak et al, Mol. Cell. Biol.9(3): 1165-1172 (1989) describe the generation