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Msg  10307 of 10558  at  9/22/2022 9:36:07 AM  by

JBWIN


Building IP: BMY/Five Prime Patent Appl. re "PSGL-1 Antagonists and Uses Thereof"

 
United States Patent Application20220298258
Kind CodeA1
Johnston; Robert J. ; et al.September 22, 2022

PSGL-1 Antagonists and Uses Thereof

Abstract

Methods of identifying and using PSGL-1 antagonists are provided. Such methods include, but are not limited to, methods of treating cancer. PSGL-1 antagonists include, but are not limited to, antibodies that bind PSGL-1 and antibodies that bind VISTA, wherein the antibodies inhibit PSGL-1 binding to VISTA, e.g., at acidic pH (e.g., pH 6.0), as well as PSGL-1 and VISTA extracellular domain polypeptides.


Inventors:Johnston; Robert J.; (San Mateo, CA) ; Rankin; Andrew; (Redwood City, CA) ; Krishnakumar; Arathi; (Chesterfield, NJ) ; Sheppard; Paul O.; (Granite Falls, WA) ; Rajpal; Arvind; (San Francisco, CA)
Applicant:
NameCityStateCountryType

Bristol-Myers Squibb Company
Five Prime Therapeutics, Inc.

Princeton
Thousand Oaks

NJ
CA

US
US
Assignee:Bristol-Myers Squibb Company
Princeton
NJ

Five Prime Therapeutics, Inc.
Thousand Oaks
CA

Family ID:1000006391452
Appl. No.:17/695081
Filed:March 15, 2022

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
16476814Jul 9, 201911306150
PCT/US2018/013171Jan 10, 2018
17695081
62445071Jan 11, 2017

Current U.S. Class:1/1
Current CPC Class:C07K 2319/30 20130101; C07K 2317/55 20130101; C07K 2317/56 20130101; C07K 2317/54 20130101; C07K 2317/24 20130101; C07K 2319/32 20130101; C07K 16/2896 20130101; A61K 45/06 20130101; C07K 2317/76 20130101
International Class:C07K 16/28 20060101 C07K016/28

Claims



1. A method of treating cancer and/or of inhibiting binding of PSGL-1 to VISTA in a subject, comprising administering to the subject an effective amount of at least one PSGL-1 antagonist.

2. The method of claim 1, wherein the method further comprises administering to the subject an effective amount of a therapeutic agent selected from chemotherapeutic agents, anti-angiogenesis agents, growth inhibitory agents, immune-oncology agents, and anti-neoplastic compositions.

3. The method of claim 1, wherein the PSGL-1 antagonist is selected from a PSGL-1 antibody and a VISTA antibody.

4.-5. (canceled)

6. The method of claim 3, wherein the antibody is selected from a chimeric antibody, a humanized antibody, a human antibody, and an antibody fragment selected from an Fv, a single-chain Fv (scFv), a Fab, a Fab', and a (Fab').sub.2.

7.-8. (canceled)

9. The method of claim 3, wherein the PSGL-1 antagonist is an antibody that blocks binding of PSGL-1 to VISTA, at a pH in the range of pH 5.5 to pH 6.5.

10. The method of claim 3, wherein the PSGL-1 antagonist is an antibody that binds to VISTA at a pH in the range of pH 5.5 to pH 6.5 or an antibody that binds to PSGL 1 at a pH in the range of pH 5.5 to pH 6.5.

11. The method of claim 3, wherein the antibody binds to VISTA or PSGL-1 with a K.sub.D of 10 nM or less.

12.-38. (canceled)

39. A method of inhibiting binding of PSGL-1 to VISTA on a cell comprising contacting the cell with at least one PSGL-1 antagonist.

40. The method of claim 39, wherein the cell is in vitro.

41. The method of claim 39, wherein the PSGL-1 antagonist is selected from a PSGL-1 antibody and a VISTA antibody.

42.-43. (canceled)

44. The method of claim 41, wherein the antibody is selected from a chimeric antibody, a humanized antibody, a human antibody, and an antibody fragment selected from an Fv, a single-chain Fv (scFv), a Fab, a Fab', and a (Fab').sub.2.

45.-46. (canceled)

47. The method of claim 41, wherein the PSGL-1 antagonist is an antibody that blocks binding of PSGL-1 to VISTA at a pH in the range of pH 5.5 to pH 6.5.

48. The method of claim 41, wherein the PSGL-1 antagonist is an antibody that binds to VISTA at a pH in the range of pH 5.5 to pH 6.5 or an antibody that binds to PSGL-1 at a pH in the range of pH 5.5 to pH 6.5.

49. The method of claim 41, wherein the antibody binds to VISTA or PSGL-1 with a K.sub.D of 10 nM or less.

50.-65. (canceled)

66. A PSGL-1 antagonist, which inhibits at least partially the binding of VISTA to PSGL-1, at a pH in the range of pH 5.5 to pH 6.5.

67. The PSGL-1 antagonist of claim 66, which inhibits by at least 90% the binding of VISTA to PSGL-1, at a pH in the range of pH 5.5 to pH 6.5.

68.-69. (canceled)

70. The PSGL-1 antagonist of claim 66, wherein the antagonist is selected from a PSGL-1 antibody and a VISTA antibody.

71.-72. (canceled)

73. The PSGL-1 antagonist of claim 70, wherein the antibody is selected from a chimeric antibody, a humanized antibody, a human antibody, and an antibody fragment selected from an Fv, a single-chain Fv (scFv), a Fab, a Fab', and a (Fab').sub.2.

74.-75. (canceled)

76. A composition comprising a PSGL-1 antagonist of claim 66.

77.-78. (canceled)
Description



[0001] This application is a divisional of U.S. patent application Ser. No. 16/476,814, filed Jul. 9, 2019, which is a national stage application of International Patent Application No. PCT/US2018/013171, filed Jan. 10, 2018, which claims priority to U.S. Provisional Application No. 62/445,071 filed Jan. 11, 2017, each of which is incorporated in their entirety by reference herein.

TECHNICAL FIELD

[0002] Methods of identifying and using PSGL-1 antagonists are provided. Such methods include, but are not limited to, methods of treating cancer. PSGL-1 antagonists include, but are not limited to, antibodies that bind PSGL-1 and antibodies that bind VISTA, wherein the antibodies inhibit PSGL-1 binding to VISTA, e.g., at acidic pH (e.g., pH 6.0).

SEQUENCE LISTING

[0003] The present application is filed with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled "2018-01-10_01134-0058-00PCT_Final_Seq_List ST25.txt" created on Jan. 10, 2018, which is 49,152 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

BACKGROUND

[0004] V-region Immunoglobulin-containing Suppressor of T cell Activation (VISTA) is a cell surface-expressed protein that negatively regulates the activity of T cells (Wang et al., 2011, JEM 208(3) 577). VISTA is a single pass type-I transmembrane protein with a single extracellular IgV domain. Notably, the extracellular domain of VISTA bears homology to B7 family members such as PDL1, which also plays a role in modulating immune responses (Wang et al., 2011, JEM 208(3) 577). VISTA expression is restricted to hematopoietic cells and is present on monocytes, T cells and a fraction of dendritic cells (Wang et al., 2011, JEM 208(3) 577 & Flies et al., 2011, JI 187:1537). Treatment with VISTA:Ig in vitro suppresses proliferation and cytokine production by CD4+ T cells (Wang et al., 2011, JEM 208(3) 577). A VISTA specific monoclonal antibody can elicit enhanced T cell division in response to antigens presented by VISTA-expressing dendritic cells (Wang et al., 2011, JEM 208(3) 577). In vivo treatment of tumor-bearing animals with an anti-VISTA monoclonal antibody elicited an immune mediated anti-tumor response that inhibited tumor growth (Wang et al., 2011, JEM 208(3) 577). Collectively, these results highlight the importance of VISTA as a regulator of T cell-driven immune responses such as those observed during immune mediated tumor rejection. The cognate binding partner for VISTA is currently unknown.

[0005] Identification of binding partners for VISTA would assist in the understanding of VISTA-mediated inhibition of T-cell activation, and provide many advantages to drug development including selection of therapeutically effective and safe therapeutics, biomarkers for patient selection and companion diagnostics, targets for combination therapy, and new targets for developing cancer immunotherapeutic agents.

SUMMARY

[0006] In some embodiments, methods of identifying PSGL-1 antagonists are provided. In some embodiments, a method comprises contacting a candidate molecule with a VISTA molecule (e.g., a mature VISTA protein or a fragment thereof) and a PSGL-1 molecule (e.g., a mature PSGL-1 protein or fragment thereof), wherein the VISTA molecule comprises VISTA, a VISTA extracellular domain ("ECD"), or a VISTA ECD fusion molecule (e.g., excluding a signal sequence; i.e., a mature VISTA or fragment thereof), and the PSGL-1 molecule comprises PSGL-1, PSGL-1 ECD, or PSGL-1 ECD fusion molecule (e.g., excluding a signal sequence; i.e., a mature PSGL-1 or fragment thereof), wherein the contacting occurs in acidic pH, e.g., pH<7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In some embodiments, a method comprises forming a composition comprising a candidate molecule, a VISTA molecule, and PSGL-1 molecule, wherein the VISTA molecule comprises VISTA, a VISTA ECD, or a VISTA ECD fusion molecule, and the PSGL-1 molecule comprises PSGL-1, PSGL-1 ECD, or PSGL-1 ECD fusion molecule, e.g., at acidic pH, e.g., pH <7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In some embodiments, a method further comprises detecting binding of the VISTA molecule to the PSGL-1 molecule. In some embodiments, a reduction in the binding of the VISTA molecule to the PSGL-1 molecule in the presence of the candidate molecule as compared to the binding of the VISTA molecule to the PSGL-1 molecule in the absence of the candidate molecule indicates that the candidate molecule is PSGL-1 antagonist. In some embodiments, binding of the VISTA molecule to the PSGL-1 molecule is reduced by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% in the presence of the candidate molecule. In some embodiments, binding of the VISTA molecule to the PSGL-1 molecule is detected by a method selected from surface plasmon resonance, ELISA, amplified luminescent proximity homogeneous assay (ALPHA), and flow cytometry.

[0007] In any of the methods of identifying PSGL-1 antagonists described herein, the PSGL-1 antagonist may be an antibody that binds to VISTA, e.g., at acidic pH, e.g., pH<7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In any of the methods of identifying PSGL-1 antagonists described herein, the PSGL-1 antagonist may be an antibody that binds PSGL-1. In any of the methods of identifying PSGL-1 antagonists described herein, the PSGL-1 antagonist may be a small molecule. In any of the methods of identifying PSGL-1 antagonists described herein, the PSGL-1 antagonist may be a small peptide.

[0008] In some embodiments, methods of determining whether a VISTA antibody is PSGL-1 antagonist are provided. In some embodiments, a method comprises contacting the VISTA antibody with a VISTA molecule and PSGL-1 molecule, wherein the VISTA molecule comprises VISTA, a VISTA ECD, or a VISTA ECD fusion molecule, and the PSGL-1 molecule comprises PSGL-1, PSGL-1 ECD, or PSGL-1 ECD fusion molecule, e.g., at acidic pH, e.g., pH<7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In some embodiments, a method comprises forming a composition comprising the VISTA antibody, a VISTA molecule, and PSGL-1 molecule, wherein the VISTA molecule comprises VISTA, a VISTA ECD, or a VISTA ECD fusion molecule, and the PSGL-1 molecule comprises PSGL-1, PSGL-1 ECD, or PSGL-1 ECD fusion molecule, e.g., acidic pH, e.g., pH<7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In some embodiments, a method further comprises detecting the binding of the VISTA molecule to the PSGL-1 molecule. In some embodiments, a reduction in the binding of the VISTA molecule to the PSGL-1 molecule in the presence of the VISTA antibody as compared to the binding of the VISTA molecule to the PSGL-1 molecule in the absence of the VISTA antibody indicates that the VISTA antibody is PSGL-1 antagonist. In some embodiments, binding of the VISTA molecule to the PSGL-1 molecule is reduced by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% in the presence of the VISTA antibody. In some embodiments, binding of the VISTA molecule to the PSGL-1 molecule is detected by a method selected from surface plasmon resonance, ELISA, amplified luminescent proximity homogeneous assay, and flow cytometry.

[0009] In any of the methods of identifying PSGL-1 antagonists described herein, the VISTA molecule may be VISTA expressed on the surface of a cell and/or the PSGL-1 molecule may be PSGL-1 expressed on the surface of a cell.

[0010] In some embodiments, methods of inhibiting binding of PSGL-1 to VISTA in a subject are provided. In some embodiments, a method comprise administering to the subject at least one PSGL-1 antagonist. In some embodiments, methods of inhibiting binding of PSGL-1 to VISTA on a cell are provided. In some embodiments, a method comprises contacting the cell with at least one PSGL-1 antagonist, e.g., at acidic pH, e.g., pH<7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In some embodiments, the cell is in vitro.

[0011] In some embodiments, methods of treating cancer are provided. In some embodiments, a method comprises administering to a subject with cancer an effective amount of at least one PSGL-1 antagonist. In some embodiments, the method further comprises administering to the subject an effective amount of a therapeutic agent selected from chemotherapeutic agents, anti-angiogenesis agents, growth inhibitory agents, immune-oncology agents, and anti-neoplastic compositions. In any of the embodiments described herein, PSGL-1 antagonist may block binding of PSGL-1 to VISTA.

[0012] In any of the embodiments described herein, a method may comprise administering a PSGL-1 antagonist selected from PSGL-1 antibody and a VISTA antibody, wherein the antibody inhibits binding of PSGL-1 to VISTA, e.g., at acidic pH, e.g., pH<7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In any of the embodiments described herein, a method may comprise administering a PSGL-1 antibody that inhibits binding of PSGL-1 to VISTA, e.g., at acidic pH, e.g., pH<7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In any of the embodiments described herein, an antibody may be selected from a chimeric antibody, a humanized antibody, and a human antibody. In any of the embodiments described herein, an antibody may be an antibody fragment. In some embodiments, the antibody fragment is selected from an IgG (e.g., IgG1, IgG2 or IgG4), Fv, a single-chain Fv (scFv), a Fab, a Fab', and a (Fab').sub.2.

[0013] In some embodiments, uses of PSGL-1 antagonists for treating cancer in subjects are provided. In any of the uses described herein, the PSGL-1 antagonist may be a PSGL-1 antibody or a VISTA antibody, wherein the antibody inhibits binding of PSGL-1 to VISTA, e.g., at acidic pH, e.g., pH<7.0, .ltoreq.6.8, .ltoreq.6.5 or .ltoreq.6.3 or at pH 5.5 to 6.5, 6.0-6.5, 6.5-7.0 or 6.0-7.0, e.g., pH 6.0. In some embodiments, the antibody is selected from a chimeric antibody, a humanized antibody, and a human antibody. In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody fragment is selected from an IgG (e.g., IgG1, IgG2 or IgG4), Fv, a single-chain Fv (scFv), a Fab, a Fab', and a (Fab').sub.2.

[0014] Any embodiment described herein or any combination thereof applies to any and all methods of the invention described herein.


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