Search

RU-2861707-C2 - ANTI-TNF ALPHA AND NGF ANTIBODIES FOR VETERINARY USE

RU2861707C2RU 2861707 C2RU2861707 C2RU 2861707C2RU-2861707-C2

Abstract

FIELD: biotechnology. SUBSTANCE: provided are: a caninised anti-TNFa antibody and a method for producing same, a nucleic acid encoding the antibody, a host cell for producing the antibody, a pharmaceutical composition for treating a dog suffering from a TNFa-associated condition, and a method for treating a TNFa-associated condition in a dog. Also disclosed are a method for maintaining remission of a TNFa-associated condition in a dog, a method for reducing TNFa signalling function in a cell, and a method for detecting TNFa in a companion animal sample. EFFECT: treats canine inflammatory conditions, such as inflammatory bowel disease, as well as treats canine pain, such as osteoarthritis pain, back pain, cancer pain and/or neuropathic pain. 19 cl, 1 dwg, 4 tbl, 9 ex

Inventors

  • PIERCE, Stephanie, A.
  • PRESTA, LEONARD
  • LI, SHYR, JIANN
  • NGUYEN, LAM
  • CHIN, RICHARD
  • ZHAN, HANGJUN

Dates

Publication Date
20260508
Application Date
20211217
Priority Date
20201218

Claims (20)

  1. 1. An antibody that binds to canine TNFα, wherein the antibody is a caninized antibody comprising:
  2. A) a light chain variable domain containing:
  3. (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1;
  4. (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and
  5. (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 3;
  6. B) the variable domain of the heavy chain, containing:
  7. (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4;
  8. (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5; and
  9. (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6.
  10. 2. The antibody of claim 1, wherein the antibody comprises LC-FR2 containing glutamine at position 3 and lysine at position 8.
  11. 3. The antibody according to claim 1 or 2, wherein LC-FR2 comprises the amino acid sequence of SEQ ID NO: 45.
  12. 4. The antibody according to any one of claims 1-3, wherein the antibody comprises:
  13. (i) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 43 or SEQ ID NO: 46,
  14. (ii) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 22.
  15. 5. The antibody of any one of the preceding claims, wherein the antibody comprises a canine heavy chain constant region and/or a canine light chain constant region.
  16. 6. The antibody of any one of the preceding claims, wherein the antibody comprises a canine heavy chain constant region selected from an IgG-A, IgG-B, IgG-C and IgG-D constant region.
  17. 7. The antibody according to any one of claims 1-3, wherein the antibody comprises:
  18. (i) a light chain comprising the amino acid sequence of SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 38, or SEQ ID NO: 44; and
  19. (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 23 or SEQ ID NO: 64.
  20. 8. The antibody of any one of claims 1-7, wherein the antibody comprises:

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/127,994, filed December 18, 2020, and U.S. Provisional Patent Application No. 63/128,804, filed December 21, 2020, the entire contents of each of which are incorporated herein by reference. FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES [0002] The present invention relates to caninized anti-TNF alpha antibodies and/or caninized anti-NGF antibodies, for example, for the treatment of inflammatory conditions in canines, such as inflammatory bowel disease, and/or for the treatment of pain in canines. BACKGROUND OF THE INVENTION [0003] TNF is a cytokine that is involved in systemic inflammation and stimulates the acute phase response. TNF stimulates the inflammatory response, which in turn causes or contributes to many of the clinical problems associated with autoimmune disorders, such as ankylosing spondylitis, asthma, cancer, Crohn's disease, inflammatory bowel disease (IBD), juvenile idiopathic arthritis, psoriasis, including plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, and other chronic inflammatory disorders. [0004] The present invention relates to methods and compositions for treating diseases, such as IBD, in companion animals using antibodies against TNFα and thus relates to the fields of biology, molecular biology and veterinary medicine. [0005] Companion animals such as cats, dogs, and horses suffer from many diseases similar to those in humans, including autoimmune diseases, cancer, and chronic inflammatory disorders. However, to date, there has been no demonstration that adalimumab or infliximab can be used to treat such diseases in companion animals. Furthermore, proteins with significant human amino acid sequence content, particularly if those sequences are derived from antibodies, may be immunogenic in non-human animals. And human drugs that bind human TNF may not bind companion animal TNF in a manner that provides the same beneficial therapeutic effect in the companion animal as it does in humans, particularly if the companion animal TNF differs in sequence from human TNF. Similarly, if a human drug elicits an immune response in a companion animal, it may not be effective. See Mauldin et al., Aug. 2010, 21 (4): 373-382. [0006] IBD is a collective term used to describe a disorder of the gastrointestinal tract in dogs with associated histologic evidence of inflammation. See Ettinger SJ and Feldman EC. Diseases of the Small Intestine. Textbook of Veterinary Internal Medicine: Diseases of the Dog and the Cat, Elsevier Saunders, 2010. While the exact etiology of IBD in canines remains unknown, alterations in immune tolerance to dietary antigens and intestinal bacteria are thought to play a major role, as is a genetic predisposition. IBD in canines may share a similar etiology with the disorder that occurs in humans (also known as Crohn's disease and ulcerative colitis), but the clinical syndrome and histologic changes associated with dogs and humans are different. See Ettinger and Feldman; Suchodolski JS et al. "The fecal microbiome in dogs with acute diarrhea and idiopathic inflammatory bowel disease." PLoS ONE. 2012; 7(12): e51907. doi: 10.1371/journal.pone. 0051907; Suchodolski JS. Companion-animals symposium: Microbes and gastrointestinal health of dogs and cats." J Anim Sci. 2010; 89(5):1520-1530. Clinically, IBD in canines is characterized by persistent or recurrent signs such as vomiting, diarrhea, abdominal pain, weight loss, or changes in appetite. [0007] Accurate diagnosis of IBD in canines can be challenging, and the term "idiopathic" is often used when a precise etiologic factor cannot be identified. A complete history and physical examination, followed by laboratory testing, imaging, and intestinal biopsy (to demonstrate the presence of inflammation) are generally recommended. Furthermore, dogs with lymphocytic-plasmacytic colitis (LPC), a common form of IBD, fail to express a predominant cytokine profile (including TNFα) in the mucosa of the inflamed colon, unlike IBD in humans. See Tamura Y et al. "Evaluation of Selected Cytokine Gene Expression in Colonic Mucosa from Dogs with Idiopathic Lymphocytic-plasmacytic Colitis." J Vet Med Sci. 2014;76(10):1407-10. Therapeutic management of these patients includes antiparasitic agents (anthelmintics), antibiotics, dietary modification, and immunosuppressive medications, with remission of clinical signs being the goal. See Ettinger and Feldman. In humans, anti-inflammatory monoclonal antibodies that inhibit TNF are widely used to treat this disease. In the present authors' canine patients, the prognosis and response to traditional therapy vary and can range from excellent to poor. Thus, treatment outcomes in dogs cannot be predicted from those in humans. [0008] Thus, there remains a need for methods and compounds that can be used to bind companion animal TNF in companion animals