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BR-122026002420-A2 - Isolated antagonistic antibodies or antigen-binding portion thereof that bind specifically to PD-1, and pharmaceutical composition.

BR122026002420A2BR 122026002420 A2BR122026002420 A2BR 122026002420A2BR-122026002420-A2

Abstract

The present invention relates to antibodies that bind specifically to PD-1, polynucleotides encoding the antibodies or fragments, and methods for producing and using them.

Inventors

  • Raluca Verona
  • Gordon Powers
  • NINA CHI SABINS
  • NIKKI A. DEANGELIS
  • KARLA R. WIEHAGEN
  • Sandra Santulli-Marotto
  • Sheng-Jiun Wu
  • Catherine Ferrante
  • Enrique Zudaire Ubani

Assignees

  • JANSSEN BIOTECH, INC.

Dates

Publication Date
20260310
Application Date
20161101
Priority Date
20151103

Claims (9)

  1. 1. Isolated antagonist antibody that binds specifically to PD-1 or its antigen-binding portion, characterized in that it comprises a) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively; b) VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65; and/or c) HC of SEQ ID NO: 74 and LC of SEQ ID NO: 75.
  2. 2. Pharmaceutical composition, characterized in that it comprises the antibody or antigen-binding moiety thereof, as defined in claim 1, and a pharmaceutically acceptable carrier.
  3. 3. Antibody or antigen-binding portion thereof, according to claim 1, characterized in that the antibody is a bispecific antibody comprising a first domain that specifically binds to PD-1 and a second domain that specifically binds to TIM-3.
  4. 4. Bispecific antibody or antigen-binding portion thereof, according to claim 3, characterized in that a) the first domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively; and b) the second domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively; or SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively.
  5. 5. Antibody or antigen-binding portion thereof according to claim 4, characterized in that the bispecific antibody binds to TIM-3 within residues 32-47 of TIM-3 (WGKGACPVFECGNVVL) (SEQ ID NO: 261), optionally, it also binds within residues 50-56 of TIM-3 (DERDVNY) (SEQ ID NO: 262).
  6. 6. Antibody or antigen-binding portion thereof according to claim 5, characterized in that a) the first domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively, or the second domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 91, 99, 108, 118, 127 and 136, respectively; b) the first domain comprises VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65, and the second domain comprises VH of SEQ ID NO: 146 and VL of SEQ ID NO: 156; c) the antibody comprises a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2), and a second light chain (LC2) of the SEQ ID NOs: 186, 188, 191, and 194, respectively; d) the antibody comprises the HC1, LC1, HC2, and LC2 of the SEQ ID NOs: 186, 188, 248, and 194, respectively; e) the antibody comprises the HC1, LC1, HC2, and LC2 of the SEQ ID NOs: 241, 188, 245, and 194, respectively; and f) the antibody comprises the HC1, LC1, HC2, and LC2 of the SEQ ID NOs: 243, 188, 246, and 194, respectively.
  7. 7. Antibody or antigen-binding portion thereof, according to claim 4, characterized in that the bispecific antibody binds to TIM-3 within residues 90-102 of TIM-3 (RIQIPGIMNDEKF) (SEQ ID NO: 263), optionally, it also binds within residues 50-56 of TIM-3 (DERDVNY) (SEQ ID NO: 262).
  8. 8. Antibody or antigen-binding portion thereof, according to claim 7, characterized in that a) the first domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 66, 67, 68, 69, 70 and 71, respectively, and the second domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 97, 105, 115, 124, 133 and 143, respectively; b) the first domain comprises VH of SEQ ID NO: 64 and VL of SEQ ID NO: 65, and the second domain comprises VH of SEQ ID NO: 172 and VL of SEQ ID NO: 173; c) the antibody comprises HC1, LC1, HC2, and LC2 from SEQ ID NOs: 186, 188, 192, and 195, respectively; d) the antibody comprises HC1, LC1, HC2, and LC2 from SEQ ID NOs: 241, 188, 244, and 195, respectively; and/or e) the antibody comprises HC1, LC1, HC2, and LC2 from SEQ ID NOs: 243, 188, 247, and 195, respectively.
  9. 9. Pharmaceutical composition, characterized in that it comprises the bispecific antibody as defined in claim 4, and a pharmaceutically acceptable carrier.

Description

SEQUENCE LISTING [001] This request contains a sequence listing submitted via EFS-Web, the contents of which are incorporated herein in full for reference purposes. The ASCII text file, created on October 28, 2016, is named JBI5071WOPCT_ST25.txt and is 418 kilobytes in size. FIELD OF THE INVENTION [002] The present invention relates to antibodies that bind specifically to PD-1, polynucleotides encoding the antibodies or fragments, and methods for producing and using them. BACKGROUND OF THE INVENTION [003] The immune system is tightly controlled by a network of co-stimulatory and co-inhibitory ligands and receptors. These molecules provide secondary signals for T cell activation and provide a balanced network of positive and negative signals to enhance immune responses against infection and tumors, while limiting immunity to themselves (Wang et al., (Epub Mar. 7, 2011) J Exp Med 208(3):577-92; Lepenies et al., (2008) Endocr Metab Immune Disord Drug Targets 8:279-288). [004] Immune verification therapy, which targets co-inhibitory pathways in T cells to promote antitumor immune responses, has led to advances in the clinical treatment of cancer patients. [005] PD-1 is a negative immune checkpoint molecule that suppresses the functions of CD4+ and CD8+ T cells in the tumor microenvironment (TME). The binding of PD-1 to its ligands (PD-L1 and PD-L2) triggers T cell anergy and exhaustion in tumors by inhibiting multiple downstream T cell receptor signaling pathways, resulting in decreased T cell survival, growth, and proliferation, impaired effector function, and altered metabolism. Preclinical studies have demonstrated that blocking the PD-1 pathway can reverse T cell exhaustion and stimulate antitumor immunity. [006] The PD-1 pathway therefore contributes to the downregulation of T cell functions in the tumor microenvironment and tumor evasion through immune destruction. In the tumor microenvironment, exhausted T cells, in addition to expressing high levels of PD-1, express other inhibitory receptors including CTLA-4, TIM-3, LAG-3, CD244, TIGIT and CD160 (see, for example, Pauken &Wherry; 2015, Trends in Immunology 36(4): 265-276). [007] TIM-3 is a transmembrane receptor that is expressed on CD4+ Th1 (helper T cells) and CD8+ cytotoxic T cells that secrete IFN-γ. TIM-3 is generally not expressed on naive T cells, but instead is upregulated on activated effector T cells. TIM-3 plays a role in the regulation of immunity and tolerance in vivo (see Hastings de et al., (2009) Eur J Immunol 39(9):2492-501). [008] Antibodies to PD-1 have been described, for example, in: US Patents No. 5,897,862 and 7,488,802, and in international patent publications No. WO2004/004771, WO2004/056875, WO2006/121168, WO2008/156712, WO2010/029435, WO2010/036959, WO2011/110604, WO2012/145493, WO2014/194302, WO2014/206107, WO2015/036394, WO2015/035606, WO2015/085847, WO2015/112900 and WO2015/112805. [009] Antibodies to TIM-3 have been described, for example, in: Monney et al., Nature (2002) 415(6871):536-41, and in international patent publications no. WO2011/155607, WO2013/006490 and WO2015/117002. [0010] Combinations with an antibody for TIM-3 and an antibody for PD-L1 were evaluated, for example, in international patent publication no. WO2011/159877. [0011] While anti-PD-1/PD-L1 antibodies are demonstrating encouraging clinical responses in patients with multiple solid tumors, response rates are still quite low, around 15% to 20% in pre-treated patients (Swaika et al., (2015) Mol Immunol. doi: 10.1016/j.molimm.2015.02.009). [0012] Therefore, there is a need for new therapeutic agents that inhibit the immunosuppressive activity of checkpoint inhibitors such as PD-1 and TIM-3, to be used for cancer immunotherapy and treatment of other conditions that could benefit from enhanced immune response, such as chronic infections. BRIEF SUMMARY OF THE INVENTION [0013] The invention provides an isolated antagonist antibody that specifically binds to PD-1, comprising a complementarity-determining region of heavy chain 1 (HCDR1), an HCDR2 and an HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, or SEQ ID NOs: 82, 83 and 85, respectively. [0014] The invention also provides an isolated antagonist antibody that specifically binds to PD-1, comprising a heavy chain complementarity-determining region 1 (HCDR1), an HCDR2 and an HCDR3 of SEQ ID NOs: 82, 83 and 84, respectively, and a light chain complementarity-determining region 1 (LCDR1), an LCDR2 and an LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively. [0015] The invention also provides an isolated antagonist antibody that specifically binds to PD-1, comprising a heavy chain complementarity-determining region 1 (HCDR1), an HCDR2 and an HCDR3 of SEQ ID NOs: 82, 83 and 85, respectively, and a light chain complementarity-determining region 1 (LCDR1), an LCDR2 and an LCDR3 of SEQ ID NOs: 86, 87 and 88, respectively. [0016] The invention also provides an isolated antagonist antibody that specifically binds to P