Provided herein are methods for the clinical treatment of tumors (e.g., advanced solid tumors) in patients having certain levels of serum IL-8 using an anti-IL-8 antibody in combination with an anti-PD-1 antibody.

CROSS-REFERENCE TO RELATED APPLICATIONS

(1) This application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2019/013134, filed Jan. 11, 2019, which claims priority to U.S. Provisional Application 62/679,412, filed Jun. 1, 2018, U.S. Provisional Application 62/650,047, filed Mar. 29, 2018 and U.S. Provisional Application 62/616,716, filed Jan. 12, 2018. The contents of the aforementioned applications are hereby incorporated by reference in their entirety.

SEQUENCE LISTING

(1) The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web, and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 1, 2020, is named MXI-610US.txt and is 18,799 bytes in size.

BACKGROUND

(2) Recent advances in the development of several immune checkpoint pathway inhibitors have provided new immunotherapeutic approaches to treat cancer. Antibodies of these new class of inhibitors include, e.g., ipilimumab (YERVOY®), which binds to and inhibits Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), and nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013), which bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway. Despite the remarkable success of these agents, however, a certain population of cancer patients are refractory to or relapse following treatment with these antibodies. Accordingly, novel therapies that target this patient population are desired.

SUMMARY

(3) Provided herein are methods of treating a subject having cancer, e.g., advanced solid tumors, by administering an anti-IL-8 antibody in combination with an anti-PD-1 antibody.

(4) In one aspect, provided herein is a method of treating a solid tumor in a human subject, the method comprising administering to the subject an effective amount of each of:

(5) (a) an anti-IL-8 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8,

(6) (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 17, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 18.

(7) In some embodiments, the method comprises at least one administration cycle, wherein the cycle is a period of 4 weeks or 28 days, wherein for each of the at least one cycles, one dose of the anti-IL-8 antibody is administered at a fixed dose of 2400 mg, 1200 mg, or 600 mg, or a fixed dose of about 2400 mg, 1200 mg, or 600 mg, and one dose of the anti-PD-1 antibody is administered at a dose of 240 mg, 360 mg, or 480 mg, or a dose of about 240 mg, 360 mg, or 480 mg. In some embodiments, the anti-IL-8 antibody and anti-PD-1 antibody are administered at the following doses: (a) 2400 mg anti-IL-8 antibody and 240 mg, 360 mg, or 480 mg of anti-PD-1 antibody; (b) 1200 mg anti-IL-8 antibody and 240 mg, 360 mg, or 480 mg of anti-PD-1 antibody; or (c) 600 mg anti-IL-8 antibody and 240 mg, 360 mg, or 480 mg of anti-PD-1 antibody. In some embodiments, the treatment consists of up to 26 cycles. In some embodiments, the anti-IL-8 antibody, or anti-IL-8 antibody and anti-PD-1 antibody, are administered on Day 1 of each cycle.

(8) In some embodiments, the baseline serum IL-8 level in the subject is above the lower limit of quantitation, for example, at least or greater than 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, g2 pg/mL, or 1 pg/mL, as assessed by, e.g., ELISA (e.g., sandwich ELISA). In some embodiments, the baseline serum IL-8 level in the subject is >10 pg/mL. In some embodiments, the baseline serum IL-8 level in the subject is >5 pg/mL. In some embodiments, the cancer has progressed or relapsed after anti-PD-1 or anti-PD-L1 therapy.

(9) In some embodiments, the anti-IL-8 antibody, or anti-IL8 antibody and anti-PD-1 antibody, are formulated (together or separately) for intravenous administration. In some embodiments, the anti-IL-8 antibody is administered prior to administration of the anti-PD-1 antibody, e.g., within about 30 minutes prior to administration of the anti-PD-1 antibody.

(10) In some embodiments, the methods described herein produce at least one therapeutic effect chosen from a reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, and stable disease. In some embodiments, the methods described herein produce at least one therapeutic effect chosen from prolonged survival, such as progress free survival or overall survival, optionally compared to another therapy or placebo.

(11) In some embodiments, the methods described herein are used to treat a solid tumor (e.g., a metastatic, recurrent, and/or unresectable tumor) is associated with a cancer selected from the group consisting of: melanoma, non-small cell lung carcinoma, renal cell carcinoma, triple negative breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma.

(12) In some embodiments, the anti-IL-8 antibody comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 1-3 and 4-6, respectively; heavy and light chain variable region sequences set forth in SEQ ID NOs: 7 and 8, respectively; or heavy and light chain sequences set forth in SEQ ID NOs: 9 and 10, respectively. In some embodiments, the anti-PD-1 antibody comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 11-13 and 14-16, respectively; heavy and light chain variable region sequences set forth in SEQ ID NOs: 17 and 18, respectively; or heavy and light chain sequences set forth in SEQ ID NOs: 19 and 20, respectively.

(13) In another aspect, provided herein is a method of treating a solid tumor in a human subject, the method comprising (i) determining the baseline serum IL-8 level in the human subject; (ii) if the human subject has a baseline serum IL-8 level of at least 5 pg/mL, administering to the subject an effective amount of each of an anti-IL-8 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8, (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 17, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 18. In some embodiments, the human subject has a baseline serum IL-8 level of at least 10 pg/mL. In some embodiments, the human subject has a baseline serum IL-8 level between 10 pg/mL and 50 pg/mL, between 10 pg/mL and 25 pg/mL, or less than or equal to 23 pg/mL. In another aspect, provided herein is a method of determining likelihood of response of a human subject having a solid tumor to a therapy containing an anti-PD-1 antibody, comprising determining the baseline serum IL-8 level of the human subject; herein the human subject is likely to respond to the therapy if the baseline serum IL-9 level is between 10 pg/mL and 50 pg/mL. In some embodiments, the human subject is likely to respond to the therapy if the baseline serum IL-9 level is between 10 pg/mL and 25 pg/mL. In some embodiments, the human subject is likely to respond to the therapy if the baseline serum IL-9 level is less than or equal to 23 pg/mL.

(14) In another aspect, provided herein is a kit for treating a solid tumor in a human subject, the kit comprising a dose of an anti-IL-8 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8, and a dose of an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 17, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 18, and instructions for use. In some embodiments, the anti-IL-8 antibody in the kit comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 1-3 and 4-6, respectively, and the anti-PD-1 antibody in the kit comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 11-13 and 14-16, respectively.