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KR-102963112-B1 - Pharmaceutical composition for treating cancer comprising polypeptide derived from Mycobacterium tuberculosis

KR102963112B1KR 102963112 B1KR102963112 B1KR 102963112B1KR-102963112-B1

Abstract

The present invention relates to a polypeptide derived from Mycobacterium tuberculosis or a variant thereof and a pharmaceutical composition for treating cancer containing the same. The pharmaceutical composition according to the present invention can be applied as an anticancer agent by specifically binding to ASC to induce multimerization of ASC and thereby activating the NLRP3 inflammasome.

Inventors

  • 양철수
  • 김효근

Assignees

  • 한양대학교 에리카산학협력단

Dates

Publication Date
20260512
Application Date
20230808
Priority Date
20230601

Claims (13)

  1. An ASC-specific binding molecule comprising the sequence represented by SEQ ID NO. 1, which specifically binds to ASC (Apoptosis-associated Speck-like protein containing a CARD).
  2. In claim 1, the binding molecule is an ASC-specific binding molecule composed of the sequence represented by SEQ ID NO. 1.
  3. In claim 1, the binding molecule is an ASC-specific binding molecule comprising the sequence represented by SEQ ID NO. 2.
  4. An ASC-specific binding molecule according to claim 1, wherein the amino acids at the 2nd, 7th, 10th, and 13th positions of SEQ ID NO. 1 are not substituted.
  5. An ASC-specific binding molecule that does not include L2F, L7F, N10T, and N13T substitutions in claim 4.
  6. delete
  7. A pharmaceutical composition for cancer treatment comprising an ASC-specific binding molecule according to any one of claims 1 to 5.
  8. A pharmaceutical composition for treating cancer according to claim 7, wherein the cancer is inflammatory colorectal cancer, colorectal cancer, melanoma, or hepatocellular carcinoma.
  9. A nucleic acid molecule expressing an ASC-specific binding molecule of any one of claims 1 to 5.
  10. A pharmaceutical composition for cancer treatment comprising the nucleic acid molecule of claim 9.
  11. A pharmaceutical composition for treating cancer according to claim 10, wherein the cancer is inflammatory colorectal cancer, colorectal cancer, melanoma, or hepatocellular carcinoma.
  12. A recombinant vector comprising the nucleic acid molecule of claim 9.
  13. Isolated host cell comprising the nucleic acid molecule of claim 9.

Description

Pharmaceutical composition for treating cancer comprising polypeptide derived from Mycobacterium tuberculosis The present invention relates to a polypeptide derived from Mycobacterium tuberculosis that specifically binds to ASC, and a pharmaceutical composition for treating cancer containing the same. It is known that over 200 types of cancer have been identified in humans. Cancer claims the lives of millions of people worldwide every year, and the incidence of cancer is on the rise due to population aging. Anticancer drugs have evolved in form with technological advancements; they are commonly classified into first-generation chemotherapy drugs, second-generation targeted therapy drugs, third-generation immunotherapy drugs, and fourth-generation metabolic therapy drugs. First-generation anticancer drugs operate on the principle of killing cancer cells or tissues by administering substances that exhibit cytotoxicity or act on biological signals. These drugs utilize metabolic inhibitors, alkylating agents, platinum-based agents, antibiotics, and hormone therapies; however, they present a problem of various side effects because they can also act on normal tissues. Targeted therapy drugs were developed to minimize side effects by acting specifically on cancer cells, but they suffered from limited targets and the development of drug resistance. Consequently, immunotherapy drugs, which eliminate cancer cells by enhancing innate immune responses, and metabolic therapy drugs, which eliminate cancer cells by blocking their nutrient supply, have been proposed. ASC or PYCARD proteins have been found in aggregate form in human leukemia cells treated with chemotherapy drugs. It is known that in many tumor patients, ASC is methylated, which inhibits apoptosis and the role of ASC as a tumor suppressor. Consequently, ASC has been identified as a key protein in the formation of the NLRP3 inflammasome complex, which mediates the secretion of inflammatory cytokines IL-1β and IL-18. Meanwhile, human NLRP3 inflammasome signaling is controlled by various factors, such as genetic polymorphisms and mutations, which influence gene expression and can ultimately lead to activation. These effects have been observed in patients with inflammatory diseases (erma D, S rndahl E, Andersson H, Eriksson P, Fredrikson M, J nsson JI, et al. The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and L-18 production. LoS ne. 2012) :e34977.; Touitou I, Lesage S, McDermott M, Cuisset L, Hoffman H, Dode C, et al. Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutat. (2004) 24:194-8.; Levy R, G rard L, Kuemmerle-Deschner J, Lachmann HJ, Kon -Paut I, Cantarini L, et al. Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis. (2015) 74:2043-9.; Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. (2001) 29:301-5.). Similarly, genetic polymorphisms associated with the NLRP3 inflammasome are also associated with cancer. For example, the single-nucleotide polymorphism (SNP) Q705K (rs35829419) of the NLRP3 gene is associated with reduced survival rates in patients with invasive colorectal cancer (Ungerb ck J, Belenki D, Jawad ul-Hassan A, Fredrikson M, Frans n K, Elander N, et al. Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and LRP3-inflammasome signaling effect usceptibility and result for olorectal cancer. Arcinogenesis. 2012) 3:2126-34), and was estimated as a risk allele for sporadic metastatic melanoma in Swedish men (Verma D, Bivik C, Farahani E, Synnerstad I, Fredrikson M, Enerb Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma. Pigment Cell Melanoma Res. (2012) 25:506-13), and it also occurred with high frequency in pancreatic cancer patients (Miskiewicz A, Szparecki G, Durlik M, Rydzewska G, Ziobrowski I, G rska R. The Q705K and F359L single-nucleotide polymorphisms of NOD-like receptor signaling pathway: association with chronic pancreatitis, pancreatic cancer, and periodontitis. Arch Immunol Ther Exp (Warsz). (2015) 63:485-94). In addition, individuals with NLRP3 polymorphisms (rs10754558 and rs4612666) were found to be more susceptible to gastric cancer when infected with Helicobacter pylori (Casta o-Rodr guez N, Kaakoush NO, Goh KL, Fock KM, Mitchell HM. The NOD-like receptor signaling pathway in Helicobacter pylori infection and related gastric cancer: a case-control study and gene expression analyses. PLoS One. (2014) 9:e98899). Polymorphisms localized to IL-1β and IL-18 in hematological malignancies have been shown to be associated with the clinical and pathophysiological characteristics of AML and chronic myeloid leukemia (CML) (Zhang A, Yu J, Yan S, Zhao X, Chen