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JP-7856768-B2 - MAb11-22.1 complex, an anti-TfR1 antibody for cancer treatment.

JP7856768B2JP 7856768 B2JP7856768 B2JP 7856768B2JP-7856768-B2

Inventors

  • ルゥ メイソン
  • マ チンホン

Assignees

  • ノースイースト ファーマスーティカル グループ カンパニー リミテッド

Dates

Publication Date
20260511
Application Date
20221203
Priority Date
20211206

Claims (18)

  1. A binder conjugate comprising a light chain variable region and a heavy chain variable region , a binder targeting T fR1 , and an antitumor agent bound to the binder , The CDR1 to CDR3 in the light chain variable region each have the same sequence as sequence numbers 5, 6, and 7 , respectively, The heavy chain variable regions CDR1 to CDR3 each have the same sequence as sequence number 8, sequence number 9, and sequence number 10, respectively. A binder complex .
  2. The binder complex according to claim 1 , having at least 70% of the same light chain variable region as SEQ ID NO: 2.
  3. The binder complex according to claim 1 , having at least 70% of the heavy chain variable region identical to that of SEQ ID NO: 4.
  4. The binder conjugate according to claim 1, wherein the binder is a monoclonal antibody.
  5. The conjugate conjugate according to claim 4 , wherein the monoclonal antibody is a mouse, human, humanized, chimeric, bispecific, or multispecific antibody.
  6. The binder complex according to claim 4 , wherein the binder is a diabody, a single-domain antigen-binding (SDAB) molecule, a VH or VL domain, or a VHH domain.
  7. The binder complex according to claim 4 , wherein the monoclonal antibody has an IgG1 heavy chain and a κ light chain.
  8. The binder complex according to claim 1, wherein the binder is a fragment of Fab, Fab', F(ab') 2 , rIgG, Fv, or Fd.
  9. The binder complex according to claim 1, wherein the binder is scFv or sc(Fv) 2 .
  10. The binder complex according to claim 4 , wherein the monoclonal antibody is class IgD, class IgE, class IgG, class IgA, or class IgM, or one subclass of the said class.
  11. The binder conjugate according to claim 10 , wherein the subclass of the monoclonal antibody is IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2.
  12. The binding agent complex according to claim 10 , wherein the monoclonal antibody has a κ light chain.
  13. A binder comprising a light chain variable region and a heavy chain variable region, which targets TfR1, The CDR1 to CDR3 in the light chain variable region have the same sequence as sequence number 5, sequence number 6, and sequence number 7, respectively, A binder targeting TfR1 , wherein CDR1 to CDR3 in the heavy chain variable region have the same sequence as SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively .
  14. The light chain variable region has the same arrangement as sequence number 2, Having the heavy chain variable region having the same sequence as sequence number 4 , The binder according to claim 13 .
  15. A separated DNA or RNA molecule encoding the binder described in claim 13 .
  16. The isolated DNA or RNA molecule according to claim 15 , having the nucleotide sequence of SEQ ID NO: 1.
  17. The isolated DNA or RNA molecule according to claim 15 , wherein the DNA molecule has the nucleotide sequence of Sequence ID No. 3.
  18. A vector comprising the isolated DNA or RNA molecule described in claim 15 .

Description

This invention relates to the use of antibodies for binding to transferrin receptor 1 (TfR1) and its isoforms in human cancer cells and for regulating their internalization and activity. The invention also relates to antibody-drug conjugates (ADCs) with small molecules used for the in vitro, in-situ, and/or in vivo diagnosis and/or treatment of mammalian cells or pathological conditions associated with TfR1 and its isoforms. Transferrin receptor 1 (TfR1, CD71) is a type II transmembrane glycoprotein consisting of 760 amino acids. It is linked by two disulfide bonds to form a 180-kDa homodimer, playing a crucial role in regulating iron uptake and cell growth (BOMFORD and MUNRO. Hepatology. 5:870-875, 1985). When diiron transferrin (Tf) binds to TfR1 on the cell surface, the holo-Tf-TfR1 complex is internalized by clathrin-coated pits and delivered to acidic endosomes. There, the iron-Tf-TfR1 complex undergoes a conformational change induced by low pH, followed by the release of iron and its transport into the cytoplasm. Next, the apo-Tf/TfR1 complex (apo-Tf/TfR1) returns to the cell surface through recirculation, where apo-Tf dissociates from its receptor (WARD. Invest Radio. 22:74-83, 1987; DANIELS et al. Clin Immunol. 121:144-158, 2006). TfR1 expression increases in rapidly proliferating cells that strongly require iron for heme synthesis, such as blood cells, hepatocytes, and keratinocyte precursors, but its expression decreases or is absent in non-dividing cells. TfR1 is overexpressed in primary and metastatic cancer cells originating from lymphocytes, pancreas, stomach, colon, lung, breast, bladder, and skin (GATTER et al. J Clin Pathol. 36:539-545, 1983; FAULK et al. Lancet. 2:390-392, 1980; SUTHERLAND et al. Proc Natl Acad Sci USA 78:4515-4519, 1981; DANIELS et al. Clin Immunol. 121:144-158, 2006; JEONG et al. Biochem Biophys Res (Commun. 471:373-379, 2016; Peer et al. Nat Nanotechnol. 2:751-760, 2007; Qian et al. Pharmacol Rev. 54:561-587, 2002; Richardson et al. Biochim Biophys Acta Gen Subj. 1790:702-717, 2009). Since cancer cells are thought to be more sensitive to iron deprivation, targeting Tf or TfR1 by blocking iron binding or interfering with the internalization of the holo-Tf/TfR1 complex can induce iron deprivation and kill malignant cells. The literature over the past 30 years has described numerous attempts to treat malignancies by developing anti-human TfR1 antibodies or TfR1-binding peptides to compete with TfR1 in interfering with receptor binding or internalization (see, for an overview, Tortorella and Karagianis. J Member Biol. 247:291-307, 2014; Candelaria et al. Front. Immunol. 17 March 2021. doi.org/10.3389/fimmu.2021.607692). TROWBRIDGE and LOPEZ (Proc. Natl Acad Sci USA, 79, 1175-1179, 1982; U.S. Patent No. 4,434,156) reported a mouse anti-TfR1 antibody named 42/6 that can inhibit the growth of human T-cell leukemia cell lines in vitro by blocking the binding of Tf and TfR1 through a non-competitive mechanism. While 42/6 was well-tolerated in patients during a Phase Ia clinical trial, its lack of efficacy was observed because, as a mouse IgA isotype, it induced human anti-mouse antibodies (HSMS) and was rapidly eliminated by the kidney (BROOKS et al. Clin Cancer Res. 1:1259-1265, 1995). MOURA et al. A more potent neutralizing mouse anti-TfR1 IgG2b antibody (A24) has been reported (J Exp Med, 194, 417-425, 2001) that directly competes with TfR1 by binding with high affinity ( KD = 2.7 nM), thereby reducing TfR expression and inhibiting T cell proliferation by inhibiting TfR recirculation. In contrast to 42/6, which exerts its antiproliferative effect by inhibiting cells during the S phase of the cell cycle, A24 acts by inducing apoptosis in target cells, inhibiting the extracorporeal proliferation of adult T-cell leukemia/lymphoma (ATLL), acute myeloid leukemia (AML), and mantle cell lymphoma (MCL) cells (Moura et al. Blood. 103:1838-1845, 2004; CALLENS et al. Leukemia. 22:42-48, 2008; LEPELLETIER. Cancer Res. 67:1145-1154, 2007). In recent years, several chimeric antibodies, humanized antibodies, or fully human antibodies have been developed to overcome the lack of efficacy in humans and the HAMA response. For example, the mouse-human IgG3 chimeric antibody ch128.1 has shown in vivo anticancer activity in cell line-derived xenotransplantation (CLDX) models of human multiple myeloma (MM) and AIDS-associated non-Hodgkin lymphoma (AIDS-NHL) (DANIELS.J Immunother. 34:500-508, 2011; DANIELS-WELLS.J Immunother. 38:307-310, 2015.), and its humanized version, hu128.1 (IgG1), is also potent in the AIDS-NHL CLDX model (DANIELS-WELLS. Cancer Res. 80(16 Suppl):5655, 2020.). The anticancer activity of ch128.1 and hu128.1 is thought to depend on Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cell-mediated cytotoxicity (CDC), and antibody-dependent cell-mediated phagocytosis (ADCP). Three fully human neutralizing antibodies for IgG1 isotypes have been de