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EP-4104853-B1 - ARGININE DEIMINASE WITH REDUCED CROSS-REACTIVITY TOWARD ADI - PEG 20 ANTIBODIES FOR CANCER TREATMENT

EP4104853B1EP 4104853 B1EP4104853 B1EP 4104853B1EP-4104853-B1

Inventors

  • SHOWALTER, RICHARD
  • ALMASSY, ROBERT
  • THOMSON, JAMES A.
  • SISSON, Wes
  • SHIA, Wei-Jong
  • CHEN, LI-CHANG
  • LEE, YANG

Dates

Publication Date
20260506
Application Date
20150916

Claims (10)

  1. An isolated arginine deiminase, or a fragment thereof having ADI activity, wherein the isolated arginine deiminase has reduced cross-reactivity with patient anti-ADI-PEG 20 antibodies, wherein the isolated arginine deiminase comprises the amino acid sequence set forth in SEQ ID NO: 22, or a variant that displays at least 90% sequence identity to SEQ ID NO: 22, and wherein the arginine deiminase is covalently bonded via a linker to a PEG molecule.
  2. The isolated arginine deiminase of claim 1, wherein the isolated arginine deiminase has one or more properties comparable to or better than those of ADI-PEG 20; optionally wherein the one or more properties is Kcat, Km, pH optimum, stability, in vivo proteolytic stability, or no requirement for ions or cofactors that are not already present in blood, or any combination thereof.
  3. The isolated arginine deiminase of claim 1 or claim 2, wherein (a) the isolated arginine deiminase comprises the amino acid sequence set forth in SEQ ID NO: 22; (b) the isolated arginine deiminase has been modified to remove at least one pegylation site; and/or (c) at least one lysine residue has been modified by an amino acid substitution, optionally wherein at least 5, 10,15, or 20 lysine residues have been modified by an amino acid substitution.
  4. The isolated arginine deiminase of any one of claims 1-3, wherein the arginine deiminase is covalently bonded to more than one PEG molecule, 1 to 10 PEG molecules, or 2 to 8 PEG molecules; optionally wherein the PEG molecules are straight chain or branch chain PEG molecules; optionally wherein the PEG has a total weight average molecular weight of from 1,000 to 40,000, or from 10,000 to 30,000.
  5. The isolated arginine deiminase of any one of claims 1-4, wherein the linker is a succinyl group, an amide group, an imide group, a carbamate group, an ester group, an epoxy group, a carboxyl group, a hydroxyl group, a carbohydrate, a tyrosine group, a cysteine group, a histidine group, a methylene group, or any combinations thereof; optionally wherein the source of the succinyl group is succinimidyl succinate.
  6. A therapeutic composition comprising the isolated arginine deiminase, or a fragment thereof, of any one of claims 1-5, and a pharmaceutically-acceptable carrier.
  7. The therapeutic composition of claim 6, further comprising a chemotherapeutic agent, optionally wherein the chemotherapeutic agent is selected from the group consisting of docetaxel, carboplatin, cyclophosphamide, gemcitabine, cisplatin, sorafenib, sunitinib and everolimus.
  8. The isolated arginine deiminase of any one of claims 1-5 or the therapeutic composition of claims 6 or 7, for use in a method of treating, ameliorating the symptoms of, or inhibiting the progression of a cancer.
  9. The isolated arginine deiminase or the therapeutic composition for use according to claim 8, wherein (a) the patient in need thereof has been determined to have anti-ADI-PEG 20 antibodies; and/or (b) the cancer is selected from the group consisting of hepatocellular carcinoma, melanoma, metastatic melanoma, pancreatic cancer, prostate cancer, small cell lung cancer, mesothelioma, lymphocytic leukemia, chronic myelogenous leukemia, lymphoma, hepatoma, sarcoma, leukemia, acute myeloid leukemia, relapsed acute myeloid leukemia, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, glioma, glioblastoma multiforme, non-small cell lung cancer (NSCLC), kidney cancer, bladder cancer, uterine cancer, esophageal cancer, brain cancer, head and neck cancers, cervical cancer, testicular cancer, and stomach cancer.
  10. The isolated arginine deiminase or the therapeutic composition for use according to claim 8, wherein the method of treating comprises administering to a patient in need thereof a therapeutically effective amount of a composition comprising ADI-PEG 20, and after a period of time, administering to the patient the therapeutic composition or arginine deiminase, thereby treating, ameliorating the symptoms of, or inhibiting the progression of the cancer, optionally wherein the period of time is determined by: detecting a predetermined level of anti-ADI-PEG 20 antibodies in the patient, wherein the therapeutic composition is administered following detection of the predetermined level of said anti-ADI-PEG 20 antibodies; or detecting ADI activity in the patient, wherein the therapeutic composition is administered following detection of a predetermined or reduced level of ADI activity.

Description

BACKGROUND Technical Field The present invention relates to arginine deiminase (ADI) proteins having reduced cross-reactivity with ADI-PEG 20 antibodies. Such ADI proteins are useful for treating arginine-dependent or related diseases such as cancer. Description of the Related Art Amino acid deprivation therapy can be an effective treatment of some forms of cancer. To date, there is one known clinical example relevant to this approach which utilizes asparaginase to lower circulating levels of asparagine and inhibit protein synthesis. This treatment is particularly effective for acute lymphoblastic leukemia (Avramis 2005, Viera Pinheiro 2004). Acute lymphoblastic leukemia cells require the amino acid asparagine for growth and proliferation. In contrast, most normal human cells are capable of synthesizing asparagine and are unaffected by asparagine depletion. Therefore, decreasing serum asparagine with asparaginase can selectively kill the cancer cells without harming the normal cells, tissues, and host. An E. coli derived form of asparaginase has been approved for human use. However, asparaginase is found only in microbes; which makes it highly immunogenic in humans and also has a short serum half-life following injection (Avramis 2005). To make asparaginase a more effective drug, these drawbacks were minimized by formulating the E. coli derived asparaginase with polyethylene glycol (PEG) to reduce the immunogenicity of this enzyme and the associated allergic reactions. In addition, PEG greatly prolongs the circulating half-life of asparaginase, which reduces both the frequency of treatment and the total cost of the therapy. PEG formulated asparaginase is approved for use and is marketed under the trade name Oncaspar® (Oncaspar® 2011, Avramis 2005, Viera Pinheiro 2004, Fu 2007, Zeidan 2008). Arginine is another non-essential amino acid for humans and mice (for review see Rogers 1994). In humans, arginine can be synthesized from citrulline in two steps via the Krebs (urea) cycle enzymes argininosuccinate synthetase (ASS, L-citrulline:L-aspartate ligase [AMP-forming], EC 6.3.4.5) and argininosuccinate lyase (ASL, L-argininosuccinate arginine-lyase, EC 4.3.2.) (Haines 2011, Wu 2009, Morris 2006, Husson 2003, Tapiero 2002, Rogers 1994). ASS catalyzes the conversion of citrulline and aspartic acid to argininosuccinate, which is then converted to arginine and fumaric acid by ASL. An arginine deficient diet in humans does not evoke hyperammonemia, orotic aciduria, nor alter the rate of whole body nitric oxide (NO) synthesis in adult humans (Tapiero 2002, Castillo 1995, Rogers 1994, Carey 1987, Barbul 1986, Snyderman 1959, Rose 1949). Although preterm infants appear to require arginine (Wu 2004), arginine levels do not correlate with age among infants, children and young adults (Lucke 2007). In 1992, Takaku and Sugimura separately reported that human melanomas and hepatocellular carcinoma (HCC) cell lines appear to require arginine for growth. Other studies showed that pegylated ADI was effective for the treatment of melanomas and hepatomas with few adverse effects. ADI-PEG 20 treatment requires multiple doses over a period of time. After a number of treatments, anti-ADI-PEG 20 antibodies can develop that may limit its continued effectiveness. Therefore, there is a need in the art for ADI that has reduced cross-reactivity to anti-ADI-PEG20 antibodies for use in treatment in order to improve and extend the efficacy of arginine depletion therapy. The present invention provides this and other advantages for the treatment of cancers. WO 2014/151982 A2 describes an arginine deiminase with reduced cross-reactivity toward ADI-PEG20 antibodies for cancer treatment. US 2012/148559 A1 discloses a therapeutic composition comprising an isolated arginine deiminase (from Mycoplasma arginini), or a fragment thereof having ADI activity, and a pharmaceutically-acceptable carrier, wherein the isolated arginine deiminase has reduced cross-reactivity with patient anti-ADI-PEG antibodies and is used for cancer therapy . US 2005/129706 A1 discloses arginine deiminases derived from e.g., Mycoplasma arginini, Mycoplasma hominus and Mycoplasma arthritides linked to PEG for the treatment of tumors such as melanoma. References: Avramis VI, Panosyan EH. 2005. Clin Pharmacokinet 44:367-393; Barbul A. 1986. J Parenteral Enteral Nutr 10:227-238; Carey GP, et al. 1987. J Nutr 117:1734-1739; Castillo L, et al. 1995. Am J Physiol 268 (Endocrinol Metab 31):E360-367; Fu CH, Sakamoto KM. 2007. Expert Opin Pharmacother 8:1977-1984; Haines RJ, et al. 2011. Int J Biochem Mol Biol 2:8-23; Husson A, et al. 2003. Eur J Biochem 270:1887-1899; Lücke T, et al. 2007. Clin Chem Lab Med 45:1525-1530; Morris SM Jr. 2006. Am J Clin Nutr 83(Suppl):598S-512S; Rogers QR. 1994. In Proceedings from a Symposium Honoring Willard J. Visek - from Ammonia to Cancer and Gene Expression. Special Publication 86 - April, 1994, Agriculture Experiment Station, University of Illinoi