SELECTION OF RESPONDERS FOR ANTI-BTN3A TREATMENT
The present disclosure relates to the pharmaceutical field. More specifically, it relates to methods for treating a tumor in a human subject in need thereof, said method comprising administering a therapeutically efficient amount of an anti-BTN3A antibody which induces the activation of Vγ9Vδ2 T cells, in combination with a therapeutically efficient amount of an anti-PD1/PDL1 treatment, wherein said subject is having relapsed or refractory tumors to anti-PD1/PDL1 treatment.
1 . A method for treating a tumor in a human subject in need thereof, said method comprising administering a therapeutically efficient amount of an anti-BTN3A antibody which induces the activation of Vγ9Vδ2 T cells, in combination with a therapeutically efficient amount of an anti-PD1/PDL1 treatment, wherein said subject is having relapsed or refractory tumors to anti-PD1/PDL1 treatment.
2 . The method of claim 1 , wherein said tumor is a solid tumor, in particular selected from the group consisting of bladder cancer, melanoma, non small cell lung cancer, and head and neck squamous cell carcinoma.
3 . The method of claim 1 , wherein said anti-BTN3A antibody binds to human BTN3A polypeptide with a K D of 10 nM or less, as measured by surface plasmon resonance (SPR).
4 . The method of claim 1 , wherein said anti-BTN3A antibody cross-reacts to cynomolgus BTN3A with a K D of 100 nM or less, as measured by SPR.
5 . The method of claim 1 , wherein said anti-BTN3A antibody induces in vitro the activation of Vγ9Vδ2 T cells in human PBMC, with an EC 50 below 0.1 mg/mL, as measured by surface expression of the activation markers CD69.
6 . The method of claim 1 , wherein said anti-BTN3A antibody induces the activation of Vγ9Vδ2 T cells in co-culture with BTN3 expressing cells, with an EC 50 below 5 mg/mL, as measured in a degranulation assay.
7 . The method of claim 1 , wherein said activating anti-BTN3A antibody comprises HCDR1 of SEQ ID NO:12, HCDR2 of SEQ ID NO:13, HCDR3 of SEQ ID NO:14, LCDR1 of SEQ ID NO:15, LCDR2 of SEQ ID NO:16 and LCDR3 of SEQ ID NO:17.
8 . The method of claim 1 , wherein said anti-BTN3A antibody is a humanized antibody.
9 . The method of claim 1 , wherein said anti-BTN3A antibody includes at least the following amino acid mutations in the VH framework regions: VSQ; V11L; K12V; R66K; S74F; 175S; E81Q; S82AR; R82BS; R83T; D85E; T87S; L108S; and at least the following amino acid mutations in the Vk framework regions: TSN; V15L; R18T; V19I; K42N; A43I; D70G; F73L; Q100G.
10 . The method of claim 1 , wherein said anti-BTN3A antibody comprises a mutant or chemically modified IgG1 constant region, wherein said mutant or chemically modified IgG1 constant region confers no or decreased binding to Fcγ receptors when compared to a corresponding antibody with wild type IgG1 isotype constant region.
11 . The method of claim 1 , wherein said anti-BTN3A antibody comprises a variable heavy chain (VH) of SEQ ID NO:1 and a variable light chain (VL) of SEQ ID NO:2.
12 . The method of claim 1 , wherein said anti-BTN3A antibody comprises a variable heavy chain (VH) of SEQ ID NO:1 and a variable light chain (VL) of SEQ ID NO:3.
13 . The method of claim 1 , wherein said mutant IgG1 constant region is IgG1 triple mutant L247F L248E and P350S.
14 . The method of claim 1 , wherein said anti-BTN3A antibody comprises either
(i) a heavy chain of SEQ ID NO:4 and a light chain of SEQ ID NO:6;
(ii) a heavy chain of SEQ ID NO:4 and a light chain of SEQ ID NO:7;
(iii) a heavy chain of SEQ ID NO:5 and a light chain of SEQ ID NO:6; or,
(iv) a heavy chain of SEQ ID NO:5 and a light chain of SEQ ID NO:7.
15 . The method of claim 1 , wherein said anti-BTN3A antibody is administered in combination with a cytokine.
16 . The method of claim 1 , wherein said cytokine is an IL2 or ID 5 agonist.
17 . The method of claim 1 , wherein said anti-BTN3A antibody is administered in combination with an immunotherapeutic agent.
18 . The method of claim 1 , wherein said anti-BTN3A antibody is administered in combination with an anti-PD1/anti-PD-L1 treatment selected from the group consisting of an anti-PD1 or anti-PD-L1 antibody.
19 . The method of claim 18 , wherein said anti-PD1 or anti-PD-L1 antibody is selected from the group consisting of nivolumab, pembrolizumab, avelumab, durvalumab, cemiplimab, and atezolizumab.
20 . The method of claim 18 , wherein said anti-PD1 or anti-PD-L1 antibody is pembrolizumab.
21 . The method of claim 1 , wherein the therapeutic dose of the activating anti-BTN3A antibody is within 7 and 200 mg per administration, preferably within 20 and 75 mg.
22 . The method of claim 1 , wherein said anti-BTN3A antibody comprises a heavy chain of SEQ ID NO:4 and a light chain of SEQ ID NO:6, and the therapeutic dose of the activating anti-BTN3A antibody is within 7 and 200 mg per administration and wherein said subject is administered with a therapeutically efficient amount of pembrolizumab.
23 . The method of claim 1 , wherein said anti-BTN3A antibody comprises a heavy chain of SEQ ID NO:4 and a light chain of SEQ ID NO:6, and the therapeutic dose of the activating anti-BTN3A antibody is within 20 and 75 mg.
24 . The method of claim 1 , wherein said anti-BTN3A antibody is administered intravenously at least twice at a dose comprised between 7 and 200 mg each dose, the second dose being administered at least 15 days after the first dose, typically after about 21 days.
25 . The method of claim 1 , wherein said anti-BTN3A antibody is administered at a dose selected from 7, 10, 20, 50, 75, 100, 125, 150, 170 or 200 mg.
26 . A method for enhancing immune cell infiltration in a tumor of a subject in need thereof, said method comprising administering an efficient amount of an anti-BTN3A antibody comprises a heavy chain of SEQ ID NO:4 and a light chain of SEQ ID NO:6, in combination with an efficient amount of an anti-PD1 or anti-PDL1 agent.
27 . The method of claim 26 , wherein said an anti-PD1 or anti-PDL1 agent is pembrolizumab.
28 . The method of claim 26 , wherein said immune cells comprises Vγ9Vδ2 T cells and CD8+ T cells.