JPWO2021055994A5

JPWO2021055994A5 -

Info

Publication number: JPWO2021055994A5
Application number: JP2022518264A
Authority: JP
Publication date: 2023-09-29

Claims

In tumor samples obtained from subjects in need of LAG-3 antagonist treatment, (i) LAG-3-D score, (ii) LAG-3-P score, or (iii) LAG-3-D score and LAG -3-P score: A method for identifying a human subject with cancer suitable for LAG-3 antagonist treatment, the LAG-3-D score determining whether MHCII in a tumor sample is The LAG-3-P score is determined by measuring the density of T cells expressing LAG-3 in the vicinity of one or more tumor cells expressing A method, determined by measuring the percentage of T cells expressing LAG-3 in the vicinity of tumor cells.

A composition comprising a LAG-3 antagonist for use in a method of treating cancer in a human subject in need of treatment, the subject comprising: a tumor sample obtained from the subject; D score, (ii) a high LAG-3-P score, or (iii) both a high LAG-3-D score and a high LAG-3-P score, where the LAG-3-D score is The LAG-3-P score is determined by measuring the density of T cells expressing LAG-3 in the vicinity of one or more tumor cells expressing MHCII in a tumor sample; The composition is determined by measuring the percentage of T cells that express LAG-3 in the vicinity of one or more tumor cells.

The treatment method is
(a) in a sample obtained from the subject: (i) a high LAG-3-D score, (ii) a high LAG-3-P score, or (iii) a high LAG-3-D score and a high LAG-3- 3. The composition of claim 2, comprising: identifying a subject having both a P-score; and (b) administering a LAG-3 antagonist to the subject.

(a) The LAG-3-D score is calculated by dividing (i) the number of T cells expressing LAG-3 in the vicinity of tumor cells expressing MHCII by (ii) the tumor area (mm ² ) of the tumor sample. Calculated as a value,
(b) The LAG-3-P score measures (i) the number of T cells expressing LAG-3 in the vicinity of tumor cells expressing MHCII; and (ii) T cells expressing LAG-3 in the tumor sample. Calculated as the value divided by the total number of
(c) the neighborhood is between LAG-3 and MHC class II and/or between LAG-3 and a tumor antigen expressed on a tumor cell;
(d) the neighborhood is about 50 μm or less, about 45 μm or less, about 40 μm or less, about 35 μm or less, or about 30 μm or less;
(e) the neighborhood is about 30 μm or less; or (f) a combination of the above;
4. A method according to claim 1 or a composition according to claim 2 or 3.

The tumor sample comprises one or more tumor sections obtained from a tumor tissue biopsy or tumor tissue resection, the tumor sample comprising a first tumor section stained for LAG-3, a second tumor section stained for MHCII. 5. A method according to claim 1 or 4 or a composition according to any one of claims 2 to 4, comprising a third tumor section stained for a tumor antigen.

(a) A high LAG-3-D score of at least about 5 cells/mm ² , at least about 10 cells/mm ² , at least about 15 cells/mm ² , at least about 20 cells/mm 2 ² , at least about 25 cells/mm ² , at least about 30 cells/mm ² , at least about 35 cells/mm ² , at least about 40 cells/mm ² , at least about 45 cells/mm 2 ² , at least about 50 cells/mm ² , at least about 55 cells/mm ² , at least about 60 cells/mm ² , at least about 65 cells/mm ² , at least about 70 cells/mm 2 ² , at least about 75 cells/mm ² , at least about 80 cells/mm ² , at least about 85 cells/mm ² , at least about 90 cells/mm ² , at least about 95 cells/mm 2 ² or at least about 100 cells/mm ² ,
(b) a high LAG-3-P score of at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%; %, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 100%, or (c) a combination of the above.
A method according to any one of claims 1, 4 or 5 or a composition according to any one of claims 2 to 5.

The method or claim according to any one of claims 1 or 4 to 6, further comprising measuring the state of tumor mutational burden (TMB) and/or measuring membranous PD-L1 expression in the tumor. The composition according to any one of items 2 to 6.

The method according to any one of claims 1 or 4 to 7 or the method according to any one of claims 2 to 7, wherein the tumor is PD-L1 positive and/or the tumor is LAG-3 positive. Composition of.

The method according to any one of claims 1 or 4 to 8 or the composition according to any one of claims 2 to 8, wherein the LAG-3 antagonist is a soluble LAG-3 polypeptide or an anti-LAG3 antibody. .

(a) the soluble LAG-3 polypeptide is IMP321 (efthiragimod alfa);
(b) the anti-LAG-3 antibody is a full-length antibody;
(c) the anti-LAG-3 antibody is a monoclonal antibody, chimeric antibody, humanized antibody, human antibody or multispecific antibody;
(d) the anti-LAG-3 antibody is an F(ab') ₂ fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide;
(e) the anti-LAG-3 antibody cross-competes with BMS-986016 (leratlimab) for binding to human LAG-3;
(f) the anti-LAG-3 antibody binds to the same epitope as BMS-986016 (leratlimab); ), MK-4280 (28G-10), REGN3767 (Fianlimab), TSR-033, TSR-075, Sym022, FS-118, IMP731 (H5L7BW), GSK2831781, humanized BAP050, aLAG3 (0414), aLAG3 (0416) , XmAb22841, MGD013, BI754111, P 13B02-30, AVA-017, 25F7, AGEN1746, or an antigen binding portion thereof;
10. A method according to claim 9 or a composition according to claim 9.

Any of claims 1 or 4 to 10, further comprising administering to the subject a programmed death-1 (PD-1) pathway inhibitor and/or a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor. The method according to any one of claims 2 to 10 or the composition according to any one of claims 2 to 10.

The method of claim 11 or the method of claim 11, wherein the PD-1 pathway inhibitor is an anti-PD-1 antibody and/or an anti-PD-L1 antibody, a soluble PD-L2 polypeptide, or BMS-986189. Composition.

(a) the soluble PD-L2 polypeptide is AMP-224;
(b) the anti-PD-1 antibody and/or anti-PD-L1 antibody is a full-length antibody;
(c) the anti-PD-1 antibody and/or anti-PD-L1 antibody is a monoclonal antibody, chimeric antibody, humanized antibody, human antibody, or multispecific antibody;
(d) the anti-PD-1 antibody and/or anti-PD-L1 antibody is an F(ab') ₂ fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide; be,
(e) the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1;
(f) the anti-PD-1 antibody binds to the same epitope as nivolumab;
(g) the anti-PD-1 antibody cross-competes with pembrolizumab for binding to human PD-1;
(h) the anti-PD-1 antibody binds to the same epitope as pembrolizumab;
(i) Anti-PD-1 antibodies include nivolumab, pembrolizumab, PDR001, MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI -1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or an antigen-binding portion thereof;
(j) the anti-PD-L1 antibody cross-competes with nivolumab for binding to human PD-L1;
(k) the anti-PD-L1 antibody binds to the same epitope as atezolizumab;
(l) the anti-PD-L1 antibody cross-competes with durvalumab for binding to human PD-L1;
(m) the anti-PD-L1 antibody binds to the same epitope as durvalumab;
(n) the anti-PD-L1 antibody cross-competes with avelumab for binding to human PD-L1;
(o) the anti-PD-L1 antibody binds to the same epitope as avelumab; or (p) the anti-PD-L1 antibody binds to the same epitope as avelumab; or (p) the anti-PD-L1 antibody binds to the same epitope as avelumab; BGB-A333, ICO36, CK-301 or an antigen binding portion thereof;
13. A method according to claim 12 or a composition according to claim 12.

12. The method of claim 11 or the composition of claim 11, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

Anti-CTLA-4 antibody:
(a) It is a full-length antibody,
(b) is a monoclonal antibody, chimeric antibody, humanized antibody, human antibody or multispecific antibody;
(c) is an F(ab') ₂ fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment or single chain binding polypeptide;
(d) cross-competes with ipilimumab for binding to human CTLA-4; or (e) binds to the same epitope as ipilimumab.
15. The method of claim 14 or the composition of claim 14.

LAG-3 antagonists and PD-1 pathway inhibitors and/or CTLA-4 inhibitors are formulated for intravenous administration, and/or (a) LAG-3 antagonists and PD-1 pathway inhibitors and/or or the CTLA-4 inhibitor is formulated separately;
(b) the LAG-3 antagonist and the PD-1 pathway inhibitor and/or CTLA-4 inhibitor are formulated together;
(c) the PD-1 pathway inhibitor and/or CTLA-4 inhibitor is administered before the LAG-3 antagonist;
(d) the LAG-3 antagonist is administered before the PD-1 pathway inhibitor and/or CTLA-4 inhibitor, or (e) the LAG-3 antagonist and the PD-1 pathway inhibitor and/or CTLA-4 the inhibitor is administered at the same time,
A method according to any one of claims 11 to 15 or a composition according to any one of claims 11 to 15.

the cancer is selected from the group consisting of breast cancer, hepatocellular carcinoma, gastroesophageal cancer, melanoma, bladder cancer, stomach cancer, lung cancer, kidney cancer, head and neck cancer, colon cancer and any combination thereof; the cancer is unresectable; 17. The method according to any one of claims 1 or 4 to 16 or the composition according to any one of claims 2 to 16, which is locally advanced or metastatic.

A kit for treating a subject suffering from a tumor, the kit comprising:
(a) the dosage of the LAG-3 antagonist; and (b) the LAG-3 antagonist in the method of any one of claims 1 or 4-17 or the composition of any one of claims 2-17. A kit containing instructions for use of 3 antagonists.

19. The kit of claim 18, further comprising a dose of a PD-1 pathway inhibitor.