Anti-CTLA-4 antibody dosing regimen

Abstract

The present invention relates to anti-CTLA-4 antibody dosing regimens, including for use in the treatment of cancer.

Description

[Technical field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made in part with Government support under Grant No. R44CA250824 awarded by the National Cancer Institute of the NIH. The Government has certain rights in this invention.

[0002] The present invention relates to dosing regimens for anti-CTLA-4 antibodies, including for the treatment of cancer. [Background technology]

[0003] Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152 (cluster of differentiation 152), is a cell surface protein receptor that interacts with B7-1 (CD80) and B7-2 (CD86) to ensure proper functioning of regulatory T cells and protect the host from autoinflammatory diseases. Approved antibodies, such as anti-CTLA-4 monoclonal antibodies (mAbs), ipilimumab (commercially available as YERVOY® from Bristol-Myers Squibb), have shown potent and broad cancer immunotherapy effects (CITE) in various preclinical models and are used clinically both as monotherapy and as part of combination therapy with nivolumab (anti-PD-1, commercially available as OPDIVO® from Bristol-Myers Squibb). However, CTLA-4 monotherapy is associated with more immunotherapy-related adverse effects (irAEs) than anti-PD-1 / PD-L1 therapy. Furthermore, the rate of severe irAEs (grade 3 and grade 4) reached 55% in melanoma patients receiving combination therapy with ipilimumab and nivolumab. This strong irAE further limits the number of doses that cancer patients can tolerate. Nevertheless, combination therapy with anti-PD-1 has led to significant improvements in response rates and patient survival in multiple cancer types. Furthermore, anti-CTLA-4 antibodies induce long-lasting immunity in cancer patients. Thus, CTLA-4 remains an important immunotherapy target, but significant challenges remain in improving both the safety and efficacy of anti-CTLA-4 mAbs.

[0004] ONC-392 is a highly selective humanized monoclonal IgG1 kappa isotype antibody against CTLA-4. It has been recently shown that ONC-392 can dissociate from CTLA-4 under low pH, escaping lysosomal degradation and recycling to the cell surface. There are several evidences supporting the notion that pH-sensitive antibodies such as ONC-392 are safer as well as more effective at Treg depletion and tumor rejection than pH-insensitive ipilimumab. First, by maintaining CTLA-4 on the cell surface, ONC-392 maintains a higher ligand density, resulting in better ADCC. Second, ONC-392 is more efficient at Treg depletion in the tumor microenvironment. Second, ONC-392 is significantly more potent at inducing rejection of large tumors. Nevertheless, there is a need in the art for a suitable dosing schedule to provide safe and effective treatment with ONC-392. Summary of the Invention

[0005] Provided herein is a method of administering an anti-CTLA-4 antibody, which may include administering one or more doses of an anti-CTLA-4 antibody to a subject. The subject may have cancer. Also provided herein is a method of treating cancer in a subject in need of cancer treatment, which may include administering one or more doses of an anti-CTLA-4 antibody to the subject. Further provided are an anti-CTLA-4 antibody for use in cancer treatment, a composition comprising an anti-CTLA-4 antibody for cancer treatment, and a use of an anti-CTLA-4 antibody in the manufacture of a medicament for cancer treatment. The anti-CTLA-4 antibody may be used in combination with a second anti-cancer agent, which may be pembrolizumab.

[0006] Each dose of the anti-CTLA-4 antibody administered to the subject can be independently about 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. The anti-CTLA-4 antibody can be administered about once every week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, or about once every six weeks, specifically about once every three weeks. Each dose of the anti-CTLA-4 antibody can be about 3 mg / kg, about 6 mg / kg, or about 10 mg / kg. The subject can be administered a first dose of about 10 mg / kg, a second dose of about 10 mg / kg, and one or more subsequent doses of about 1-6 mg / kg. Each subsequent dose can be about 6 mg / kg or about 3 mg / kg.

[0007] The anti-CTLA-4 antibody is administered and the peak concentration of the antibody (C- max (a) The C of the anti-CTLA-4 antibody in a blood sample obtained from the subject may be maintained at about 200 to 300 μg / mL, specifically about 225 to 250 μg / mL, more specifically 225 μg / mL or 250 μg / mL. max The dose of the anti-CTLA-4 antibody administered to the subject may be reduced compared to the previous dose if (a) the subject has a limiting toxicity of more than 225 μg / mL, 250 μg / mL, or 300 μg / mL, (b) the subject experiences a limiting toxicity, or (c) the subject is undergoing treatment for cancer and achieves a partial or complete response to treatment with the anti-CTLA-4 antibody according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The anti-CTLA-4 antibody may be administered intravenously, or the composition or medicament may be intended for intravenous administration.

[0008] The anti-CTLA-4 antibody may comprise (a) a light chain variable region comprising a complementarity determining region (CDR) 1 comprising the amino acid sequence shown in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 2 to 4, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO: 5, and (b) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence shown in SEQ ID NO: 6, a CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs: 7 to 9, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO: 10. The anti-CTLA-4 antibody may comprise a light chain variable region comprising a CDR2 comprising the sequence shown in SEQ ID NO: 3, and a heavy chain variable region comprising a CDR2 comprising the sequence shown in SEQ ID NO: 9. The anti-CTLA-4 antibody may comprise a light chain variable region comprising the sequence shown in SEQ ID NO: 12, and a heavy chain variable region comprising the sequence shown in SEQ ID NO: 16. The anti-CTLA-4 antibody may comprise a light chain comprising the sequence shown in SEQ ID NO: 23, and a heavy chain comprising the sequence shown in SEQ ID NO: 21. The anti-CTLA-4 antibody can be ONC-392.

[0009] The cancer may be a solid tumor. The cancer may be advanced or metastatic. The subject may have previously failed or been intolerant to standard treatments for the cancer. The cancer may be resistant or resistant to anti-PD-1 / PD-L1 treatment. The cancer may be melanoma, metastatic melanoma, PD(L)-1 resistant melanoma, non-small cell lung adenocarcinoma, metastatic NSCLC, NSCLC with driver mutations (e.g., EGFR / ALK mutations or other targetable mutations), PD-1 resistant NSCLC, head and neck cancer, adenoid cystic carcinoma (which may be R / M), squamous cell carcinoma, triple negative (basal type) breast cancer, pancreatic cancer, renal cell carcinoma, cervical cancer, endometrial cancer, colon cancer, hepatocellular carcinoma, other solid tumors, or metastatic colorectal cancer (which may have microsatellite instability). [Brief description of the drawings]

[0010] [Figure 1]Figure 1 shows the flow diagram for Part A, Phase IA, of the ONC-392 monotherapy clinical trial. DLT = dose-limiting toxicity, Gr = grade, Q3W = every 3 weeks, RECIST = Response Evaluation Criteria in Solid Tumors, RP2D-M = recommended Phase II dose of ONC-392 as monotherapy, TEAE = treatment-emergent adverse events.

[0011] [Diagram 2] Figure 2 shows the flow diagram for Part B Phase IA of the clinical trial of ONC-392 in combination with pembrolizumab. DLT = dose-limiting toxicity, NSCLC = non-small cell lung cancer, PD-(L)1 = programmed cell death protein 1 or its ligand, Q3W = every 3 weeks, RECIST = Response Evaluation Criteria in Solid Tumors, RP2D-C = recommended Phase II dose of ONC-392 for combination therapy (ONC-392 + pembrolizumab).

[0012] [Diagram 3] Figure 3 shows the flow diagram for Part C, Phase IB expansion of the study of ONC-392 as monotherapy (top) or in combination with pembrolizumab (bottom). ALK=anaplastic lymphoma kinase, ECOG=Eastern Cooperative Oncology Group, EGFR=epidermal growth factor receptor, IO=immunotherapy, IV=intravenous, Mel=melanoma, mu=mutated, NSCLC=non-small cell lung cancer, TNBC=triple-negative breast cancer, Q3W=every 3 weeks, RECIST v1.1=Response Evaluation Criteria in Solid Tumors version 1.1.

[0013] [Figure 4] FIG. 4 shows the best overall response versus ONC-392 monotherapy in Part A Phase IA of the clinical trial.

[0014] [Diagram 5]FIG. 5 shows the results of tumor tissue biomarker analysis of patients treated in Part A of the clinical trial of ONC-392 monotherapy. The top panel shows the results of an NSCLC patient treated with 3 mg / kg ONC-392 for 7 cycles, with CD8 (red), CD4 (green), Foxp3 (purple), and tumor cells (blue) labeled. The bottom left panel shows the pretreatment results of an ovarian cancer patient, and the bottom right panel shows the results of an ovarian cancer patient treated with 10 mg / kg ONC-392 for 4 cycles, with CD8 (red), CD4 (green), Foxp3 (purple), and tumor cells (blue) labeled.

[0015] [Figure 6] Figure 6 shows the goodness of fit of the final model.

[0016] [Figure 7] FIG. 7 shows the results of visual posterior predictive performance (VPC).

[0017] [Figure 8] Figure 8 shows simulated PK profiles for different dosing regimens: Regimen No. 1: 6 mg / kg Q3W, Regimen No. 2: 10 mg / kg Q3W, Regimen No. 3: 10 mg / kg Q4W, Regimen No. 4: 2 loading doses of 10 mg / kg + maintenance dose of 6 mg / kg Q3W. Figure 8A shows the logarithmic scale, while Figure 8B shows the normal scale. The solid lines are the median pk profiles. The shaded areas represent the 90% prediction interval.

[0018] [Figure 9A] 9A-9B show model-predicted probability of ORR versus ONC-392 steady-state exposure using maximum doses in patients receiving ONC-392 monotherapy. [Figure 9B] Same as above.

[0019] [Figure 10A]10A-10B show model-predicted probability of grade 3 or grade 4 TRAEs versus steady-state Cmin (FIG. 10A, top), Cmax (FIG. 10A, bottom), and AUC (FIG. 10B) of ONC-392 in patients receiving ONC-392 monotherapy. [Figure 10B] Same as above.

[0020] [Figure 11A] 11A to 11B show model-predicted probability of ORR versus steady-state exposure of ONC-392 at the maximum dose in NSCLC patients (monotherapy). [Figure 11B] Same as above.

[0021] [Figure 12A] 12A-12B show model-predicted probability of ORR and grade ≥ 3 TRAEs versus steady-state exposure to ONC-392 in patients with NSCLC. [Figure 12B] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The inventors have discovered that the anti-CTLA-4 antibody dosing regimens described herein provide inherently lower toxicity and higher efficacy compared to ipilimumab. With improved safety, the inventors have further demonstrated that clinical data for these regimens supports long-term dosing and clinical activity in cancer patients, including those with stage IV solid tumors. In particular, anti-CTLA-4 antibodies that can be used in the dosing regimens disclosed herein are pH-sensitive, such as ONC-392, which preserves CTLA-4 recycling and avoids lysosomal degradation.

[0023] 1.Definition The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0024] Recitation of numerical ranges herein expressly contemplates each intervening number of the same precision, for example, in the range 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and in the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6, 9, and 7.0 are expressly contemplated.

[0025] 2. Anti-CTLA-4 antibody administration regimen Provided herein is an anti-CTLA-4 antibody dosing regimen that may be suitable for anti-CTLA-4 antibodies that exhibit pH-sensitive binding to CTLA-4 and avoid lysosomal degradation.Specifically, the anti-CTLA-4 antibodies that may be used include the pH-sensitive anti-CTLA-4 antibodies described in U.S. Patent No. 10,618,960, the contents of which are incorporated herein by reference.

[0026] a. Anti-CTLA-4 antibody The anti-CTLA-4 antibody may comprise a light chain variable region comprising a complementarity determining region (CDR) 1 comprising the amino acid sequence RASENIYSNLA (SEQ ID NO: 1), a CDR2 comprising the amino acid sequence AATNLQS (SEQ ID NO: 2) (LC1), AATNLQD (SEQ ID NO: 3) (LC2) or AATSLQS (SEQ ID NO: 4) (LC3), and a CDR3 comprising the amino acid sequence QHLWGTPYT (SEQ ID NO: 5).

[0027] Each of the light chain variable regions, including LC1 to LC3, may also contain one of the following sequences:

[0028] LC1 DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLLYAATNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHLWGTPYTFGGGTKLEIK (SEQ ID NO: 11)

[0029] LC2 DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKQGKAPKLLLYAATNLQDGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQHLWGTPYTFGQGTKLEIK (SEQ ID NO: 12)

[0030] LC3 DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHLWGTPYTFGGGTKVEIK (SEQ ID NO: 13)

[0031] More specifically, each of the light chains, including LC1 to LC3, may comprise one of the following amino acid sequences:

[0032] LC1 DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLLYAATNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHLWGTPYTFGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC * (SEQ ID NO:22)

[0033] LC2 DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKQGKAPKLLLYAATNLQDGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQHLWGTPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC * (SEQ ID NO:23)

[0034] LC3 DIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHLWGTPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC * (SEQ ID NO:24)

[0035] The anti-CTLA-4 antibody may comprise a heavy chain variable region comprising a CDR1 comprising the amino acid sequence GFSLTSYGLS (SEQ ID NO:6), a CDR2 comprising the amino acid sequence YIWYDGNTNFHPSLKSR (SEQ ID NO:7) (HC1), YIWYDGNTNFHSSLKSR (SEQ ID NO:8) (HC2) or YIWYDGNTNFHSPLKSR (SEQ ID NO:9) (HC3), and a CDR3 comprising the amino acid sequence TEGHYYGSNYGYYALDY (SEQ ID NO:10).

[0036] Each of the heavy chain variable regions including HC1 to HC3 may comprise one of the following amino acid sequences:

[0037] HC1 QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGLSWIRQPPGKGLEWIGYIWYDGNTNFHPSLKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCAKTEGHYYGSNYGYYALDYWGQGTSVTVSS (SEQ ID NO: 14)

[0038] HC2 QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGLSWIRQPPGKGLEWIGYIWYDGNTNFHSSLKSRVTISKDTSKSQVSLKLSSVTAADTAVYYCAKTEGHYYGSNYGYYALDYWGQGTLVTVSS (SEQ ID NO: 15)

[0039] HC3 QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGLSWIRQPPGKGLEWIGYIWYDGNTNFHSPLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKTEGHYYGSNYGYYALDYWGQGTLVTVSS (SEQ ID NO: 16)

[0040] The anti-CTLA-4 antibody has the amino acid sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 17) The heavy chain constant region may comprise:

[0041] The heavy chain constant region may comprise one or more mutations. The one or more mutations may be selected from M135Y, S137T, T139E, S181A, E216A and K217A and combinations thereof, compared to the sequence set forth in SEQ ID NO: 17. In one example, the heavy chain constant region of the antibody comprises all six mutations. A mutant heavy chain constant region has the amino acid sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNATYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIAATISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 18) may include.

[0042] Even more specifically, the heavy chains of the anti-CTLA-4 antibodies, including the heavy chain variable regions HC1-HC3, may each comprise one of the following amino acid sequences:

[0043] HC1 QVQLQESGPGLVKPSETLSLTTCTVSGFSLTSYGLSWIRQPPGKGLEWIGYIWYDGNTNFHPSLKSRVTISKDTSKNQFSLKLSSVTAADTAVYYCAKTEGHYYGSNYGYYALD YWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNATYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI AATISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG ** (SEQ ID NO:19)

[0044] HC2 QVQLQESGPGLVKPSETLSLTTCTVSGFSLTSYGLSWIRQPPGKGLEWIGYIWYDGNTNFHSSLKSRVTISKDTTSKSQVSLKLSSVTAADTAVYYCAKTEGHYYGSNYGYYALD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNATYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI AATISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG **(SEQ ID NO:20)

[0045] HC3 QVQLQESGPGLVKPSETLSLTTCTVSGFSLTSYGLSWIRQPPGKGLEWIGYIWYDGNTNFHSPLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAKTEGHYYGSNYGYYALD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNATYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI AATISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG ** (SEQ ID NO:21)

[0046] The heavy chain amino acid sequences set forth in SEQ ID NO: 19 to SEQ ID NO: 21 may further include a C-terminal lysine (K), which may increase expression levels. The terminal lysine may be naturally cleaved during the production of the anti-CTLA-4 antibody or upon administration of the antibody.

[0047] PP4637 (LC2 / HC3): In one example, the anti-CTLA-4 antibody comprises a light chain variable region comprising a CDR1 comprising the sequence set forth in SEQ ID NO: 1, a CDR2 comprising the sequence set forth in SEQ ID NO: 3, and a CDR3 comprising the sequence set forth in SEQ ID NO: 5. The heavy chain variable region comprises a CDR1 comprising the sequence set forth in SEQ ID NO: 6, a CDR2 comprising the sequence set forth in SEQ ID NO: 9, and a CDR3 comprising the sequence set forth in SEQ ID NO: 10. Specifically, the light chain variable region may comprise the sequence set forth in SEQ ID NO: 12, and the heavy chain variable region may comprise the sequence set forth in SEQ ID NO: 16. More specifically, the light chain may comprise the sequence set forth in SEQ ID NO: 23, and the heavy chain may comprise the sequence set forth in SEQ ID NO: 21. This antibody may be referred to as ONC-392.

[0048] PP4631 (LC2 / HC1): In another example, the anti-CTLA-4 antibody comprises a light chain variable region comprising a CDR1 comprising the sequence set forth in SEQ ID NO: 1, a CDR2 comprising the sequence set forth in SEQ ID NO: 3, and a CDR3 comprising the sequence set forth in SEQ ID NO: 5. The heavy chain variable region comprises a CDR1 comprising the sequence set forth in SEQ ID NO: 6, a CDR2 comprising the sequence set forth in SEQ ID NO: 7, and a CDR3 comprising the sequence set forth in SEQ ID NO: 10. Specifically, the light chain variable region may comprise the sequence set forth in SEQ ID NO: 13, and the heavy chain variable region may comprise the sequence set forth in SEQ ID NO: 14. More specifically, the light chain may comprise the sequence set forth in SEQ ID NO: 23, and the heavy chain may comprise the sequence set forth in SEQ ID NO: 19.

[0049] PP4638 (LC3 / HC3): In a further example, the anti-CTLA-4 antibody comprises a light chain variable region comprising a CDR1 comprising the sequence set forth in SEQ ID NO: 1, a CDR2 comprising the sequence set forth in SEQ ID NO: 4, and a CDR3 comprising the sequence set forth in SEQ ID NO: 5. The heavy chain variable region comprises a CDR1 comprising the sequence set forth in SEQ ID NO: 6, a CDR2 comprising the sequence set forth in SEQ ID NO: 9, and a CDR3 comprising the sequence set forth in SEQ ID NO: 10. Specifically, the light chain variable region may comprise the sequence set forth in SEQ ID NO: 12 and the heavy chain variable region may comprise the sequence set forth in SEQ ID NO: 16. More specifically, the light chain may comprise the sequence set forth in SEQ ID NO: 24 and the heavy chain may comprise the sequence set forth in SEQ ID NO: 21.

[0050] b. Dosage regimen The anti-CTLA-4 antibody may be administered to a subject, which may be a human. The administration may be for treating cancer, as further described herein. The anti-CTLA-4 antibody may be administered systemically, which may be via injection or intravenous administration. The antibody may be administered as a monotherapy or as a combination therapy. The administration regimen may include administering one or more doses of the anti-CTLA-4 antibody. Each dose may independently be about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 3 mg / kg, about 5 mg / kg, about 6 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 50 mg / kg, or about 100 mg / kg, or an amount within a range of any two of the above amounts. The administration regimen may include periodic administration, in which one of the above doses is administered to the subject. In each cycle of administration, the dose may be different from the previous dose. The administration can include dose escalation. In one example, the anti-CTLA-4 antibody is administered about every week, about every two weeks, about every three weeks, about every four weeks, about every five weeks, or about every six weeks. Specifically, the antibody is administered about every three weeks. When describing the duration of a dosing cycle, "about" can mean ±1 day, ±2 days, or ±3 days.

[0051] Specifically, the dose of the anti-CTLA-4 antibody can be about 1 mg / kg, about 3 mg / kg, about 6 mg / kg, or about 10 mg / kg, or an amount within the range of any two of the above amounts. The dosing regimen can include two doses at 10 mg / kg, followed by extended doses of 1-6 mg / kg (i.e., each subsequent dose is 1-6 mg / kg). The extended doses can include administering a dose of 3 mg / kg or 6 mg / kg. In one example, each dose is about once every three weeks. The doses can be administered for a period of 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 30 weeks, 33 weeks, 36 weeks, 39 weeks, 42 weeks, 45 weeks, 48 ​​weeks, or 51 weeks. In one example, the anti-CTLA-4 antibody is used as a monotherapy, and the dose is 10 mg / kg administered every four weeks. In a further example, the anti-CTLA-4 antibody is combined with pembrolizumab, and the dose of the anti-CTLA-4 antibody is 3 mg / kg or 6 mg / kg administered every three weeks, which can coincide with the dosing schedule of pembrolizumab.

[0052] In another example, the pharmacokinetics of the anti-CTLA-4 antibody is monitored and the administration is adaptively adjusted to achieve a C- max Maintain the above C max The concentration may be maintained for 6 to 52 weeks. The concentration may be measured from a blood sample from the subject, which may be a serum sample or a plasma sample. In one example, the administration is adaptively adjusted to achieve a C of about 200 to 300 μg / mL, about 225 to 250 μg / mL, about 225 μg / mL, or about 250 μg / mL. max The dose may be adjusted to maintain an excessively high C max This excessively high C max can be 200 μg / mL, 225 μg / mL, 250 μg / mL or 300 μg / mL, specifically 250 μg / mL or 300 μg / mL. maxA tapered dose level is administered to the subject if the response is too high, if the subject experiences one or more limiting toxicities, or if the subject has cancer and the subject achieves a partial or complete response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

[0053] The anti-CTLA-4 antibody may be administered separately or in combination with a second therapeutic agent. The therapeutic agent may be an anti-cancer agent. In one example, the anti-cancer agent is administered on the same day as the anti-CTLA-4 antibody. Specifically, the anti-cancer agent may be an anti-PD-1 antibody or an anti-PD-L1 antibody. In a specific example, the anti-cancer agent is pembrolizumab (Keytruda). In one example, pembrolizumab is administered at 200 mg / cycle every 21 days (3 weeks). In a further example, the second therapeutic agent is administered on the same day as the anti-CTLA-4 antibody.

[0054] C. Preparation The anti-CTLA-4 antibody may be formulated in a dosage as described herein. In one example, the formulation comprises 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 50 mg / mL, or 100 mg / mL, or an amount within the ranges thereof. In one example, the amount is 5 mg / mL. The formulation may comprise 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, or 40 mM, or an amount within the range of any two of the above amounts. In one example, the amount is 20 mM. The formulations are also available in the following flavors: 7.0% (w / v), 7.1% (w / v), 7.2% (w / v), 7.3% (w / v), 7.4% (w / v), 7.5% (w / v), 7.6% (w / v), 7.7% (w / v), 7.8% (w / v), 7.9% (w / v), 8.0% (w / v), 8.1% (w / v), 8.2% (w / v), 8.3% (w / v), 8.4% (w / v), 8.5% (w / v), 8.6% (w / v), 8. The composition may contain 7% (w / v), 8.8% (w / v), 8.9% (w / v), 9.0% (w / v), 9.1% (w / v), 9.2% (w / v), 9.3% (w / v), 9.4% (w / v), 9.5% (w / v), 9.6% (w / v), 9.7% (w / v), 9.8% (w / v), 9.9% (w / v) or 10.0% (w / v) of alpha, alpha-trehalose dihydrate or an amount within a range between any two of the above amounts. In one example, the amount is 8.8%. The formulation may include 0.01 (w / v), 0.02 (w / v), 0.03 (w / v), 0.04 (w / v), 0.05 (w / v), 0.06 (w / v), 0.07 (w / v), 0.08 (w / v), 0.09 (w / v) or 0.10 (w / v) or an amount of polysorbate 80 within any two of the above amounts. In one example, the amount is 0.06%. The formulation may be at a pH of 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4 or 6.5 or within a range thereof.Components equivalent to histidine buffers, α,α-trehalose dihydrate, and polysorbate 80 for formulating antibodies are known in the art and may be used as alternatives.

[0055] 3. Cancer treatment The compositions and dosing regimens therefor may be used to treat cancer. Provided herein is a method of treating cancer in a subject in need thereof, which may comprise administering to the subject an anti-CTLA-4 antibody described herein. Also provided herein is the anti-CTLA-4 antibody for use in treating cancer, and the use of the anti-CTLA-4 antibody in the manufacture of a medicament for treating cancer. The method, use or medicament may comprise administering the anti-CTLA-4 antibody or medicament using a dosing regimen described herein.

[0056] The cancer may be a solid tumor. The cancer may be one of progressive locally advanced and metastatic cancers. The cancer may be stage IV cancer. The subject may be one who has failed or is intolerant to standard treatment guidelines, which may be the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). The cancer may be resistant or tolerant to anti-PD-1 / PD-L1 therapy. The resistance may be primary resistance or acquired resistance with disease progression following immunotherapy. Primary PD-1 resistance may be defined as disease progression within 24 weeks of initiation of anti-PD-(L)1 therapy. Acquired PD-1 resistance may be defined as disease control (CR, PR, or SD) for 24 weeks or more following initiation of anti-PD-(L)1 therapy, followed by progression 24 weeks later. The cancer may be immunotherapy naive and may be PD-L1 positive, such as by having a PD-L1 tumor ratio score of 1% or more. The cancer may be non-small cell lung cancer. In another example, the cancer is ovarian cancer, cervical cancer, gastroesophageal cancer, lung cancer or ovarian cancer.

[0057] The subject may be 18 years of age or older. The subject may have metastatic or locally advanced disease that is not suitable for local therapy. The subject may also have failed or been intolerant to established standard anti-cancer treatment, which may be other than pembrolizumab for a given tumor type. The subject may have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less.

[0058] The cancer may be a neoplasm or tumor resulting from abnormal and uncontrolled cell proliferation. The cancer may be a leukemia or lymphoma. The cancer may also include cells that have the potential to metastasize to distant sites.

[0059] The cancer may be carcinoma, such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, or skin cancer; squamous cell carcinoma; hematopoietic tumors of the lymphatic system, such as leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, or Burkitt's lymphoma; hematopoietic tumors of the myeloid system, such as acute myeloid leukemia, chronic myeloid leukemia, or promyelocytic leukemia. tumors of mesenchymal origin, such as fibrosarcoma or rhabdomyosarcoma; tumors such as melanoma, seminoma, teratoma, neuroblastoma or glioma; tumors of the central and peripheral nervous system, such as astrocytoma, neuroblastoma, glioma or schwannoma; tumors of mesenchymal origin, such as fibrosarcoma, rhabdomyosarcoma or osteosarcoma; or tumors such as melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, thyroid follicular carcinoma or teratoma.

[0060] The subject with cancer may have a histologically or cytologically confirmed diagnosis of solid tumors and progressive locally advanced or metastatic disease, or may have failed or been intolerant to established standard anti-cancer treatment, and the established standard treatment guidelines may be NCCN guidelines. The tumor may be a type of tumor for which pembrolizumab is approved as a standard treatment. The subject with cancer may have advanced or metastatic cancer, or may have disease progression after previous systemic cancer treatment. In one example, the cancer is pancreatic cancer, triple-negative breast cancer, non-small cell lung cancer (NSCLC) with epidermal growth factor mutation or other targetable mutation, PD-1 resistant NSCLC, head and neck cancer, and ovarian cancer.

[0061] The subject with the cancer may have advanced / metastatic cancer, or may be treatment-naïve, immunotherapy (IO)-naïve, or resistant / refractory (R / R) to anti-programmed cell death protein 1 or its ligand (anti-PD-(L)1). The cancer may be IO-naïve NSCLC, PD-L1 positive with a tumor proportion score (TPS) of 1% or more, IO R / R NSCLC, IO-naïve melanoma, or IO R / R melanoma. The cancer may be recurrent and / or metastatic (R / M) adenoid cystic carcinoma, which may be unsuitable for curative surgery or radiation.

[0062] The cancer may be melanoma, metastatic melanoma, PD(L)-1 resistant melanoma, non-small cell lung adenocarcinoma, metastatic NSCLC, NSCLC with a driver mutation (e.g., EGFR / ALK mutation or other targetable mutation), PD-1 resistant NSCLC, head and neck cancer, adenoid cystic carcinoma (which may be R / M), squamous cell carcinoma, triple negative (basal type) breast cancer, pancreatic cancer, renal cell carcinoma, cervical cancer, endometrial cancer, colon cancer, hepatocellular carcinoma, other solid tumors or metastatic colorectal cancer (which may have microsatellite instability).

[0063] The cancer may be due to apoptosis abnormalities. The cancer may be follicular lymphoma, carcinoma with one or more p53 mutations, hormone-dependent tumors of the breast, prostate or ovary, precancerous lesions such as familial adenomatous polyposis, or myelodysplastic syndromes. The cancer may be a malignant or dysproliferative change (such as metaplasia or dysplasia) or a hyperproliferative disorder and may be present in the ovary, bladder, breast, colon, lung, skin, pancreas or uterus. In particular, the cancer may be a sarcoma, melanoma or leukemia.

[0064] The present invention has multiple aspects, illustrated by the following non-limiting examples. EXAMPLES

[0065] Example 1 Safety and efficacy of anti-CTLA-4 antibody therapy This example demonstrates the safety and efficacy of the anti-CTLA-4 antibody ONC-392 for the treatment of cancer, specifically for the treatment of advanced solid tumors and non-small cell lung cancer (NSCLC).

[0066] Indications Part A, the Phase IA ONC-392 monotherapy dose-finding cohort will enroll patients with progressive locally advanced or metastatic disease with a histologically or cytologically confirmed diagnosis of solid tumors who have failed or are intolerant to established standard anti-cancer treatment according to standard treatment guidelines, such as the NCCN Guidelines.

[0067] The Part B Phase IA combination dose-finding cohort will enroll patients with progressive locally advanced or metastatic disease with a histologically or cytologically confirmed diagnosis of solid tumors and tumor types for which pembrolizumab is approved as a standard of care. Treatment-naïve or checkpoint inhibitor immunotherapy-naïve or checkpoint inhibitor immunotherapy-resistant / resistant patients may be enrolled.

[0068] The Part C Phase IB ONC-392 monotherapy cohort will enroll patients with advanced / metastatic cancer who have disease progression after prior systemic therapy in the following monotherapy arms: pancreatic cancer (Arm A), triple-negative breast cancer (TNBC) (Arm B), non-small cell lung cancer (NSCLC) with EGFR (epidermal growth factor receptor) mutations or other targetable mutations (Arm C), PD-1-resistant NSCLC (Arm I), head and neck cancer (Arm K), ovarian cancer (Arm L), solid tumors not eligible for the tumors designated in Arms A, B, C, I, K, and L, or tumor types other than the above (Arm M).

[0069] The Part C Phase IB combination cohort will enroll patients with advanced / metastatic cancer who are treatment-naïve, immunotherapy (IO)-naïve, or refractory / resistant (R / R) to anti-programmed cell death protein 1 or its ligand (anti-PD-(L)1) therapy into the following combination arms: NSCLC IO-naïve, PD-L1 positive, with PD-L1 Tumor Proportion Score (TPS) ≥ 1% (Arm D), NSCLC IO R / R (Arm E, any PD-L1 status), melanoma (Mel) IO-naïve (Arm F), and Mel IO R / R (Arm G).

[0070] Study Design Overview The exam consists of three related parts:

[0071] Part A (Figure 1) is a dose-finding, rapid titration study of ONC-392 monotherapy in patients with advanced solid tumors of various histologies. The purpose of this study is to determine the recommended phase II dose (RP2D-M) of ONC-392 monotherapy.

[0072] Part B (Figure 2) is a dose-finding study of ONC-392 in combination with a standard dose of 200 mg pembrolizumab to define the recommended phase II dose (RP2D-C) of ONC-392 in combination with pembrolizumab in patients with advanced solid tumors of various histologies where pembrolizumab is approved as standard of care (SOC).

[0073] Part C (Figure 3) Phase IB expansion cohorts of ONC-392 in monotherapy and in combination with pembrolizumab to determine safety and initial efficacy. Additional treatment arms may be included in subsequent protocol amendments. Monotherapy expansion cohorts for arms A, B, C, I, K, L, and M may begin after RP2D-M is determined. Expansion cohorts for arms D-G with combination therapy may begin after RP2D-C is determined.

[0074] Group A: Pancreatic cancer cohort, ONC-392 monotherapy will enroll patients with advanced / metastatic pancreatic cancer, including ampullary cancer, who have progressed after first- and second-line systemic therapy.

[0075] Arm B: TNBC cohort, ONC-392 monotherapy, will enroll patients with progressive / metastatic TNBC who have progressed after prior systemic therapy, including immunotherapy with a checkpoint inhibitor.

[0076] Arm C: NSCLC alone Cohort 1, ONC-392 monotherapy will enroll patients with advanced / metastatic NSCLC who have progressed after prior systemic therapy, including targeted therapy or checkpoint inhibitors, and who have EGFR or ALK mutations or other targetable mutations.

[0077] Group D: NSCLC IO-naïve cohort, ONC-392 / pembrolizumab combination therapy will enroll treatment-naïve or anti-PD(L)1 immunotherapy-naïve patients with PD-L1 positive (PDL1 TPS ≥ 1%), advanced / metastatic NSCLC cancer.

[0078] Arm E: NSCLC IO R / R cohort, ONC-392 / pembrolizumab combination therapy will enroll patients with advanced NSCLC / metastatic NSCLC cancer who are R / R to prior anti-PD-(L)1 immunotherapy, regardless of PD-L1 status.

[0079] Arm F: Melanoma IO-naïve cohort, ONC-392 / pembrolizumab combination therapy will enroll patients with advanced / metastatic melanoma who are treatment-naïve or checkpoint inhibitor immunotherapy-naïve. Prior systemic chemotherapy or targeted therapy is permitted.

[0080] Arm G: Melanoma IO R / R cohort, ONC-392 / pembrolizumab combination therapy will enroll patients with advanced / metastatic melanoma who are R / R to anti-PD-(L)1 immunotherapy.

[0081] Group I: NSCLC alone Cohort 2, ONC-392 monotherapy, will enroll patients with advanced / metastatic NSCLC who have progressed after prior systemic therapy, including chemotherapy or checkpoint inhibitors, and who have no EGFR, ALK or other targetable mutations. Patients must have received anti-PD-(L)1 therapy as monotherapy or combination therapy as their last line of treatment prior to enrollment. Patients may have received prior anti-CTLA-4 therapy.

[0082] Arm K: Head and Neck Cancer, ONC-392 monotherapy will enroll patients with advanced / metastatic HNSCC and other histology types other than adenoid cystic carcinoma, who have progressed after prior systemic treatment, including chemotherapy or checkpoint inhibitors or immunotherapy, and who may or may not be HPV positive.

[0083] Arm L: Ovarian cancer, ONC-392 monotherapy will enroll patients with advanced / metastatic ovarian cancer, including primary peritoneal and fallopian tube cancer, who have progressed following prior systemic treatment, including chemotherapy, targeted therapy or checkpoint inhibitors.

[0084] Arm M: Solid tumors, ONC-392 monotherapy will enroll patients with advanced / metastatic solid tumors who are not eligible for the monotherapy arms above and have disease progression following prior systemic treatment, including chemotherapy, targeted therapy, or checkpoint inhibitors.

[0085] Objectives and Evaluation Items

[0086] [Table 1-1]

[0087] [Table 1-2]

[0088] Main Study Eligibility Criteria To be eligible for the study, patients had to be 18 years of age or older, have metastatic disease or locally advanced disease not suitable for local therapy, have failed or failed to tolerate established standard anticancer treatments other than pembrolizumab for a given tumor type, or, in the opinion of the investigator, are medically ineligible for a particular form of standard treatment. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The table below shows the study eligibility criteria.

[0089] [Table 2]

[0090] Dosage / form of administration, route and administration regimen Dose escalation in monotherapy will evaluate five dose levels of ONC-392: 0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg, and 10 mg / kg. ONC-392 will be administered as an intravenous infusion over a minimum of 30 minutes for the 0.1 mg / kg, 0.3 mg / kg, and 1.0 mg / kg dose levels, and a minimum of 60 minutes for the 3.0 mg / kg dose level. The 10 mg / kg dose level requires a minimum administration time of 90 minutes for the first dose and 60 minutes for subsequent doses. The dosing interval for ONC-392 will be 21 days (every 3 weeks [Q3W]). Intrapatient dose escalation up to a maximum of 3 mg / kg will be permitted.

[0091] For the combination of ONC-392 and pembrolizumab, ONC-392 is initially administered as an intravenous infusion over at least 60 minutes, except that the first dose of ONC-392 at 10 mg / kg is administered over at least 90 minutes. At the 6.0 mg / kg ONC-392 dose level, the intravenous infusion is administered over 60 minutes. Pembrolizumab is then administered intravenously at a fixed dose of 200 mg over at least 30 minutes. Allow at least 30 minutes between the end of the ONC-392 infusion and the start of the pembrolizumab infusion. ONC-392 and pembrolizumab should not be mixed during administration. Both ONC-392 and pembrolizumab are administered Q3W.

[0092] If patients tolerate treatment, they may optionally continue study treatment (both monotherapy and combination therapy) for an additional four cycles after patients have confirmed progressive disease (PD) based on immune Response Evaluation Criteria in Solid Tumors (iRECIST).

[0093] Study treatment (both monotherapy and combination therapy) will be discontinued upon unacceptable toxicity, patient voluntary withdrawal, or 1 year (13 or 17 cycles), whichever occurs first (see section 5.7 for 1 year option).

[0094] In Parts A and B, administration of ONC-392, either alone or in combination with pembrolizumab, requires vital signs and electrocardiogram (ECG) monitoring as described in Table 3.

[0095] Part A: ONC-392, 5 dose levels (0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg, 3.0 mg / kg, 10.0 mg / kg) via intravenous infusion Q3W. Intrapatient dose escalation permitted to 3.0 mg / kg. Titration to RP2D-M. Up to a total of 17 doses over 12 months.

[0096] Part B: ONC-392 + pembrolizumab 200 mg / dose via intravenous infusion Q3W. Dose to RP2D-C. Up to a total of 17 cycles over 12 months.

[0097] Part C: Groups A-C and I, K, L, M. ONC-392 at RP2D-M by intravenous infusion according to the following dosing schedule. Treatment duration will be up to 1 year.

[0098] Part C: Groups D to G. Part B: RP2D-C of ONC-392 + 200 mg pembrolizumab by intravenous infusion Q3W. Up to a total of 17 cycles over 12 months. RP2D-C of ONC-392 is determined to be 6 mg / kg.

[0099] Planned patient numbers

[0100] Part A: A minimum of 10 and a maximum of 30 patients will be enrolled in ONC-392 monotherapy to identify RP2D-M.

[0101] Part B: Enroll a minimum of 6 and a maximum of 36 patients to receive ONC-392 in combination with pembrolizumab to identify RP2D-C. Dose taper will be discontinued if ≥3 of 6 patients experience dose-limiting toxicity at 1 mg / kg.

[0102] Part C: Expansion cohort studies will be conducted with an adaptive trial design. Futility stopping rules will be applied to each cohort. A minimum of 15 and a maximum of 30 patients will be enrolled in each expansion arm, except for Arm A, which will enroll a maximum of 30 efficacy-evaluable patients.

[0103] Part A: ONC-392 monotherapy Part A Phase IA study was conducted at five predefined dose levels of ONC-392, namely 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, and 10 mg / kg, as monotherapy by intravenous infusion every 21 days (Q3W). The study used an accelerated titration design. Intrapatient dose escalation was tested in the first patient who was administered 0.1 mg / kg, 0.3 mg / kg, and 1.0 mg / kg with no AEs. The patient was increased to 3.0 mg / kg and administered this dose for three cycles with no AEs. The second patient was initiated at 0.3 mg / kg with no AEs. Enrollment was then switched to a 3+3 design with 3.0 mg / kg and 10.0 mg / kg levels in the following protocol:

[0104] Part B: ONC-392 in combination with pembrolizumab in NSCLC Part B was designed as a Phase IA dose-escalation / deescalation study of ONC-392 in combination with pembrolizumab in two cohorts of patients with NSCLC, followed by a Phase IB expansion portion in RP2D-C.

[0105] The pembrolizumab dose was fixed at 200 mg / cycle administered every 21 days (Q3W).

[0106] Part B Phase IA study The Phase IA study was to begin with ONC-392 and pembrolizumab at 200 mg, one step lower than RP2D-M, and initially enroll six patients. The dose of ONC-392 was to be adjusted according to the following scenarios:

[0107] (1) If dose-limiting toxicity (DLT) occurred in one of six patients, RP2D-C was to be administered at a dose one level lower than RP2D-M. Or, (2) If 0 of 6 patients experienced a DLT, 6 additional patients were to be enrolled in dose level RP2D-M of ONC-392. If 1 or less of the additional 6 patients experienced a DLT, RP2D-M was to become PR2D-C. Or, (3) If DLT occurred in 2 patients before enrolling 6 patients, the dose of ONC-392 was to be tapered to the next dose level until 1 or fewer patients out of 6 treated at that dose experienced a DLT. This dose level was designated RP2D-C. If dose level 1 (0.1 mg / kg) turned out to be too toxic using the above rules, further exploration of the drug combination was to be discontinued.

[0108] Part B Phase IB study Both Part B Phase IB expansion cohorts were designed for patients with advanced NSCLC and included immunotherapy-naïve and resistant / tolerant cohorts. Six patients treated with RP2D-C in Part B Phase IA were evaluable for efficacy. One of the objectives of the expansion cohorts was to arrive at a more comprehensive safety profile of the combination of ONC-392 and pembrolizumab in RP2D-C. To ensure the safety of patients enrolled in the two expansion cohorts, Pocock-type boundaries were used to allow early discontinuation due to excess toxicity at any time point. The study was to be stopped at any time point if the incidence of DLT was significantly higher than θ=20%.

[0109] In the anti-PD(L)1 immunotherapy-naïve population, patients with advanced NSCLC who were PD-L1 positive (PD-L1 TPS ≥ 1% or as otherwise indicated for pembrolizumab) were to be included in the study. Eighteen subjects were to be enrolled in the phase IB expansion cohort.

[0110] In the anti-PD(L)1 resistant / resistant population, patients with advanced NSCLC who had disease progression or were intolerant to anti-PD(L)1-containing treatment (including monotherapy or combination therapy, or immunotherapy in combination with chemotherapy) after 4 or more cycles were to be included in the study. They could have received prior anti-CTLA-4 treatment. They could have a history of irAEs that had resolved. Eighteen subjects were to be enrolled in the phase IB expansion cohort.

[0111] Response rates for the PD-(L)1 treatment-naïve and resistant / tolerant cohorts were determined separately 6 months after first treatment.

[0112] Part A safety results The demographics of patients evaluated in Part A of the ONC-392 study are shown in the table below.

[0113] [Table 3]

[0114] The following table provides a summary of treatment-emergent adverse events (TEAEs).

[0115] [Table 4]

[0116] These results indicate that both doses of ONC-392 were generally well tolerated. Grade 3 irAEs of pancreatitis and colitis were manageable and reversible. The PR2D for monotherapy was 10 mg / kg Q3W. The best efficacy of ONC-392 monotherapy is shown in Figure 4. Figure 5 shows the results of tumor tissue biomarker analysis. The upper panel shows the results of a patient with NSCLC who received 3 mg / kg ONC-392 for 7 cycles, with CD8, CD4, Foxp3, and tumor cells shown in red, green, magenta, and turquoise, respectively. The lower left panel shows the pretreatment results of a patient with ovarian cancer, and the lower right panel shows the results of a patient with ovarian cancer who was treated with 10 mg / kg ONC-392 for 4 cycles, with CD8, CD4, Foxp3, and tumor cells shown in red, green, magenta, and turquoise, respectively.

[0117] These results indicate that ONC-392 was well tolerated. The longest dose was 11 cycles at 3 mg / kg. No DLTs or grade 3 / 4 AEs were observed at any dose during the DLT observation period. The maximum tolerated dose was not reached. The recommended phase 2 dose for monotherapy was determined to be 10 mg / kg. The following grade 3 / 4 AEs were observed in three patients after three or four cycles of treatment with 10 mg / kg ONC-392: colitis / hypokalemia (2) and pancreatitis (1). Of these three patients, two had unconfirmed complete responses and one had stable disease with a reduction in tumor burden. Other drug-related AEs were grade 1 / 2, and AEs observed in three or more patients included infusion-related reactions, pruritus, fatigue, and TSH increase.

[0118] clinical results Additionally, beneficial activity was observed in 6 of 10 patients. Two of 6 patients treated with ONC-392 at 10 mg / kg had a complete response, two of 6 patients treated with ONC-392 at 10 mg / kg had stable disease with biomarkers indicating a significant reduction in tumor burden or enhanced T cell activity in the tumor, and two of 4 patients treated with 3 mg / kg had stable disease (SD) at >7 months. At initial tumor evaluation, stable disease was observed in 7 of 10 patients and partial response was observed in 1 of 10 patients. Additionally, clinical improvement was observed in 3 patients with PD-(L)1 resistance / tolerance with NSCLC (1 patient had a complete response, 1 patient had disease control at >24 weeks and was eligible for surgery, and 1 patient had stable disease at 8 weeks and continues treatment).

[0119] Safety and efficacy conclusions ONC-392 was generally safe and well tolerated. Treatment-related AEs were manageable. The maximum tolerated dose was not reached at the 10 mg / kg dose. ONC-392 demonstrated therapeutic antitumor activity. As the first pH-sensitive monoclonal antibody that preserves CTLA-4 recycling and avoids lysosomal degradation, ONC-392 may fundamentally change the risk / benefit ratio of targeting CTLA-4 by providing improved efficacy and reduced toxicity.

[0120] Example 2 Clinical safety and efficacy results of anti-CTLA-4 antibodies administered at various doses This example shows the safety and efficacy of ONC-392 administered at 10 mg / kg Q3W for two cycles followed by 6 mg / kg Q3W for up to 12 months. This regimen was selected based on efficacy and safety information, PK, and exposure-response analyses from ongoing ONC-392 studies.

[0121] Clinical Safety and Efficacy Results of ONC-392 Monotherapy Four dosing regimens of ONC-392 monotherapy were tested: 1) Melanoma cohort (group J) received 6 mg / kg Q3W, 2) 10 mg / kg Q3W for the pancreatic cancer cohort and HNSCC cohort (groups A and K), 3) 10 mg / kg Q4W for the advanced solid tumor cohort (group M), 4) PD-1 / PD-L1 resistant NSCLC cohort and ovarian cancer cohort (arms I and L), 10 mg / kg Q3W × 2, then 6 mg / kg Q3W.

[0122] Safety data for all 153 patients who received ONC-392 monotherapy in the different treatment regimens tested appeared to be safe and generally well tolerated. Table 5 shows a summary of safety and ORR in NSCLC patients who received ONC-392 monotherapy. Eight patients in regimen #3 (10 mg / kg Q4W) were NSCLC patients who had received PD-1 / PD-L1 inhibitor therapy followed by chemotherapy. These patients had disease progression with chemotherapy before enrolling in the study. Two of them continued treatment, and no tumor response was observed in this patient group. The 34 patients receiving ONC-392 in regimen #4, the proposed treatment administration regimen, were from two groups of patients, namely 12 patients with driver mutations in group C and 22 patients with PD-1 / PD-L1 resistant NSCLC in group I. Efficacy of tumor response was observed in patients with PD-1 / PD-L1 resistant NSCLC.

[0123] As shown in Table 5, which compares the safety data of regimen no. 2, regimen no. 3, and regimen no. 4 in patients with NSCLC, regimen no. 4 (10 mg / kg Q3W × 2, followed by 6 mg / kg Q3W) had the lowest incidence of grade 3 or higher TRAEs (12%), treatment-related SAEs (12%), and TRAEs leading to discontinuation of study treatment (6%).

[0124] [Table 5]

[0125] The low rates of serious TRAEs and clinical activity support Regimen No. 4 for the presented indication. This dose selection is further supported by additional clinical pharmacology analysis outlined below.

[0126] Population pharmacokinetic results A population PK model was constructed from 420 measurable PK observations from 70 patients, including 57 patients receiving ONC-392 monotherapy and 13 patients receiving it in combination with pembrolizumab.

[0127] method Population PK Data Source PK data for ONC-392, with a cutoff date of July 8, 2022, covered doses ranging from 0.1 to 10 mg / kg administered via the intravenous (IV) route. The dataset includes 446 PK samples from 71 patients with various cancer types. Twenty-six PK samples were excluded from the analysis for one of the following reasons: 1) they were outliers, 2) they were pre-dose samples with negative time since first dose, or 3) the information on sampling time or dosing was missing or potentially incorrect (subjects 001–130). A population PK model was constructed from 420 measurable PK observations from 70 patients, including 57 patients receiving ONC-392 monotherapy and 13 patients receiving combination therapy with pembrolizumab.

[0128] Software and methods Nonlinear Mixed-Effects Modeling Software (NONMEM® version 7.4; ICON, Inc., Hanover, MD, USA), a software package for nonlinear mixed-effects analysis, was used for population PK modeling and simulation to derive exposure metrics for subsequent ER analysis. R (version 4.0.1) was used for visual review of diagnostic and full plots.

[0129] Nonlinear mixed-effects models were fitted to the concentration-time data of ONC-392 as a function of dose, time, and other subject-level covariates. One- or two-compartment models, i.e., linear or empirical target mediated drug disposition (TMDD) models, were tested.

[0130] In population PK models, covariate-parameter relationships were first evaluated graphically, and then potential covariates were examined directly. Model evolution was based on goodness-of-fit (GOF) plots, objective function values ​​(OFVs), precision and validity of PK parameter estimates, and visual post-hoc predictive performance assessment (VPC).

[0131] Summary of baseline covariates A summary of baseline continuous and categorical covariates is shown in Tables 6 and 7.

[0132] [Table 6]

[0133] [Table 7]

[0134] Population PK results The PK of ONC-392 is best described by a two-compartment model with first-order elimination. The total body clearance (CL) of ONC-392 was estimated to be 182 mL / day (Table 8), with a terminal t 1 / 2was estimated to be 25.7 days. Baseline albumin was identified as a significant covariate for CL, with increasing albumin levels correlating with decreasing CL. Body weight was identified as a significant covariate for volume terms including central volume (V1) and peripheral volume (V2), with increasing body weight correlating with increasing V1 and V2. No effects of age, sex, race, AST, bilirubin, creatinine clearance, or cancer type on the PK of ONC-392 were detected. None of these covariates were considered to be clinically significant. Of note, concurrent chemotherapy with PD-1 was not a significant PK covariate.

[0135] [Table 8]

[0136] In the Part C cohort expansion of this clinical trial, infrequent PK sampling was performed at approximate peak and trough times in patients receiving one of four treatment regimens.

[0137] The goodness of fit (GOF) of the final model indicated that the model fitting was reasonable, with sufficient agreement between the observed and model predictions. The residual plots did not indicate any mis-specification of the model (Figure 6). The visual posterior predictive performance (VPC) results showed adequate predictability of the final model (Figure 7).

[0138] The PK profiles observed at various dose levels of ONC-392 indicate that the proposed dosing regimen of 10 mg / kg Q3W × 2 + 6 mg / kg Q3W results in systemic concentrations reaching steady-state levels after the second dose and maintaining high trough levels throughout the dosing period (Figure 8), which is much higher than the Kd of ONC-392 (1.95 μg / mL, based on in vitro binding to human CTLA-4), ensuring adequate ONC-392 exposure in the tumor environment to maximize the antitumor activity of ONC-392.

[0139] Exposure-Response (ER) Analysis Deriving Exposure Metrics A final population PK model for ONC-392 was used to predict concentration-time profiles based on posterior Bayesian estimates. Steady-state exposure simulated by the model was used as a PK metric to assess preliminary relationships between exposure and efficacy / safety outcomes. Patient data with PK (N=70) from preliminary results of study ONC-392-001 will be used for efficacy and safety analyses. Of the 70 patients with exposure data, 57 received ONC-392 monotherapy, of which 17 were NSCLC patients.

[0140] Data used in the exposure-response (ER) analysis are summarized in Table 9.

[0141] [Table 9]

[0142] Due to the limited number of patients, the results of this preliminary ER analysis should be interpreted with caution.

[0143] Exposure-Response Relationships in Patients Treated with ONC-392 Monotherapy Tumor assessment data were available for 36 patients who received monotherapy and had PK data. Eight of these patients had a clinical response (PR or CR). The probability of ORR appears to increase with increasing exposure (C min,ss , C max,ss and AUC ss ) (Figures 9A-B). Such a correlation is consistent with the notion that a higher Cmax of ONC-392 is required to more efficiently eliminate regulatory T cells in the tumor environment. max,ss was of utmost importance to

[0144] The relationship between exposure and safety was also examined. Safety data were available for 57 patients who received ONC-392 monotherapy and had available PK data. The exposure parameters examined (C min,ss , C max,ssor AUC ss Regardless of the dose, no clear correlation was observed between the frequency or severity of drug-related TEAEs and steady-state exposure (Figures 10A-B), suggesting that exposure is not a determinant of serious TRAEs within the exposure range examined.

[0145] Exposure-response relationships in patients with NSCLC Tumor assessment data were available for 12 NSCLC patients who received monotherapy and had PK data. Exposure-response analysis showed no statistically significant associations, although there was a statistically non-significant association with exposure (C max, The results suggest a tendency for the probability of ORR to increase with increasing AUCss (Figures 11A to 11B). min、ss No relationship was observed.

[0146] However, in NSCLC patients (N=17), patients with higher steady-state exposure tended to have a higher probability of grade 3 or higher TRAEs (Figures 12A-B). Comparing safety data from patients in arms I (PD(L)1-resistant NSCLC) and L (ovarian cancer) who received the same ONC-392 regimen of 10 mg / kg Q3W × 2 followed by 6 mg / kg Q3W, NSCLC patients had a lower incidence of grade 3 or higher TRAEs (13.0% grade 3, 0% grade 4-grade 5) compared to the ovarian cancer cohort (40% grade 3, 3.3% grade 4, 0% grade 5, cutoff date 31 August 2022). The difference between the data from NSCLC (Figures 12A-B) and the data from 57 pooled patients with various tumor types (Figures 10A-B) indicates that the C-cell counts in the pooled dataset (e.g., patients with other cancer types) were significantly higher than in the NSCLC patients with similarly low exposure compared to the NSCLC patients. max,ss This is due to the high rate of TRAEs among patients with creatinine levels <300 μg / mL. The fact that NSCLC patients are less likely to develop serious TRAEs at lower exposures is consistent with the notion that higher exposures are required to develop TRAEs in this population.

[0147] overview In the Part C cohort expansion of this clinical trial, a small number of PK samplings were performed at approximate peak and trough times in patients receiving one of four treatment regimens.The PK profiles observed with various dose levels of ONC-392 demonstrated that the proposed dosing regimen of 10 mg / kg Q3W x 2 + 6 mg / kg Q3W achieved systemic concentrations at steady-state levels after the second dose and maintained median trough levels nearly 40-fold higher than the Kd of ONC-392 (1.95 μg / mL, based on in vitro binding to human CTLA-4).

[0148] In particular, preliminary efficacy data in patients receiving either 10 mg / kg Q3W or a loading dose of 10 mg / kg + maintenance dose of 6 mg / kg Q3W are encouraging. All responders had PR or CR at the first or second tumor evaluation, and the majority of responders were identified at the first tumor evaluation. This suggests that the initial exposure may play an important role in anticancer treatment with ONC-392. Therefore, we selected a high loading dose of 10 mg / kg Q3W × 2 to ensure adequate ONC-392 exposure in the tumor during the initial treatment cycle to maximize the antitumor activity of ONC-392. At the same time, the maintenance dose of 6 mg / kg Q3W helps maintain the efficacy of ONC-392 for long-term use and minimize toxicity.

[0149] C max It is noteworthy that no significant increase in the probability of ORR was observed until the dose reached approximately 225 μg / ml, a level readily achievable by regimens #2 through #4, but marginally achievable by regimen #1 used in dose expansion, and not achievable by the 3 mg / kg used in dose escalation.

[0150] In NSCLC patients (N=17) with both safety and PK data, higher steady-state exposure (C max、ssPatients with ≥ 100% CI, 0.01 to 0.25% were also more likely to have grade 3 or higher TRAEs (Figures 8A-B, lower panels). The fact that NSCLC patients with lower exposures were less likely to develop severe TRAEs suggests that the lower maintenance dose of regimen #4 may allow for better patient safety over the long term.

[0151] In the dose escalation and dose expansion parts of this study, the safety and efficacy of ONC-392 monotherapy was evaluated in approximately 130 patients at five different dose / administration regimens with increasing levels of exposure: 3 mg / kg Q3W, 6 mg / kg Q3W, 10 mg / kg Q3W, 10 mg / kg Q4W, and 10 mg / kg x 2 followed by 6 mg / kg Q3W. Based on clinical outcomes and pharmacology data, including results from exposure-response modeling, 10 mg / kg x 2 followed by 6 mg / kg Q3W was deemed the optimal dose and selected for the Phase 3 patient development stage. The rationale for the dosing regimens is summarized below.

[0152] Exposure / dose response is the probability of ORR being C max correlates best with C max Based on the inflection point of the curve showing the relationship between -ORR, C max These results suggest that a gradient of rapid increase in the establishment of ORR occurred after the initial dose reached approximately 225 μg / ml. As shown in Table 10, this threshold is immediately achievable with a starting dose of 10 mg / kg, but never with 3 mg / kg Q3W. In fact, no clinical benefit was observed in 4 patients with 3 mg / kg, despite long-term administration for up to 9 cycles and the best safety profile. With 6 mg / kg Q3W, it takes 6 cycles to reach this level. Because patients who did not respond to systemic immunotherapy had a poor prognosis, a regimen with a delay of almost 4 months to achieve a potentially effective dose is unlikely to provide meaningful clinical benefit.

[0153] [Table 10]

[0154] Of regimens #2 to #4, which are expected to provide therapeutic activity, regimen #4 was selected based on clinical data and PK. Regimen #2, 10 mg / kg Q3W, which provides the highest exposure, showed clinical activity but also the highest toxicity compared to other doses / regimens. As a result, among patients receiving 10 mg / kg Q3W, 50% (3 of 6) of patients in Part A (dose escalation) of the study and 39% (16 of 41) of patients in Part C dose expansion developed grade 3 or grade 4 TRAEs. Two of two patients with PD(L)1-resistant NSCLC treated with this regimen developed grade 3 TRAEs. For this reason, the regimen was not selected due to safety concerns.

[0155] Of the other two regimens starting at 10 mg / kg, namely regimen no. 3 (10 mg / kg Q4W) and regimen no. 4 (loading dose 10 mg / kg Q3W × 2, followed by a maintenance dose of 6 mg / kg Q3W), the earlier and higher C max Regimen #4 achieved a higher dose, while regimen #3 provided a more sustained exposure. Both regimens showed comparable clinical activity (ORR 13-14%) across all cancer types. It is noteworthy that regimen #4 achieved an ORR of 30% and DCR of 70% in 10 evaluable patients at the first and second tumor evaluations in patients with PD(L)-1-resistant NSCLC. These data suggest that a dose of 10 mg / kg Q3W×2 followed by 6 mg / kg may provide meaningful clinical benefit. Preliminary results from this trial showed that tumor responses were primarily observed at the first tumor evaluation after 2 or 3 cycles, suggesting that the first two doses of 10 mg / kg may be important and necessary to obtain a response.

[0156] More importantly, the safety of regimen no. 4 for the proposed indication appears to be highly favorable, as only 4 of 34 (11.8%) NSCLC patients developed grade 3 TRAEs and none developed grade 4 or grade 5 TRAEs (Table 6). max According to the correlation between the risk of severe TRAEs and the sustained high exposure provided by regimen #3, it is possible that the long-term safety risk is increased.

[0157] In conclusion, preliminary exposure-response results and clinical safety and efficacy findings suggest that the dosing regimen of 10 mg / kg Q3W × 2 followed by 6 mg / kg Q3W is likely to offer the best risk / benefit ratio.

Claims

1. 1. A therapeutic agent for use in a method of treating a subject, comprising an anti-CTLA-4 antibody, said method comprising administering one or more doses of the anti-CTLA-4 antibody to the subject, wherein each dose is independently 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg.

2. The therapeutic agent described in claim 1, wherein in the method, the anti-CTLA-4 antibody is administered once every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks.

3. The therapeutic agent described in Claim 2, wherein in the method, the anti-CTLA-4 antibody is administered once every three weeks.

4. A therapeutic agent described in any one of claims 1 to 3, wherein in the method, each dose of the anti-CTLA-4 antibody is 6 mg / kg.

5. The therapeutic agent according to claim 1, wherein each dose of the anti-CTLA-4 antibody is 10 mg / kg.

6. The therapeutic agent of claim 1, wherein the method comprises administering a first dose of 10 mg / kg, a second dose of 10 mg / kg, and one or more subsequent doses of 1 to 6 mg / kg.

7. The therapeutic agent described in claim 6, wherein in the method, each subsequent dose is 6 mg / kg.

8. The therapeutic agent described in claim 6, wherein in the method, each subsequent dose is 3 mg / kg.

9. The therapeutic agent according to claim 1, wherein the anti-CTLA-4 antibody is administered to maintain a peak concentration (Cmax) of 200 to 300 μg / mL in the method.

10. The therapeutic agent described in claim 9, wherein the maintained Cmax in the method is 225 μg / mL to 300 μg / mL, wherein the maintained Cmax in the method may be 225 μg / mL to 250 μg / mL.

11. The therapeutic agent according to claim 9, wherein the dose of the anti-CTLA-4 antibody administered to the subject is reduced compared to the immediately preceding dose if (a) the Cmax concentration of the anti-CTLA-4 antibody in a blood sample obtained from the subject exceeds 300 μg / mL, (b) the subject is observed to have limiting toxicity, or (c) the subject is undergoing treatment for cancer and achieves a partial or complete response to treatment with the anti-CTLA-4 antibody according to the criteria of Response Evaluation Criteria in Solid Tumors (RECIST) 1.

1.

12. The therapeutic agent according to any one of claims 1 to 3, wherein the anti-CTLA-4 antibody is administered intravenously in the method.

13. The anti-CTLA-4 antibody (a) a light chain variable region comprising a complementarity determining region (CDR) 1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 2 to 4, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5; and (b) a heavy chain variable region comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6, CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 7 to 9, and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10; The therapeutic agent according to any one of claims 1 to 3, comprising:

14. The therapeutic agent of claim 13, wherein the anti-CTLA-4 antibody comprises a light chain variable region comprising a CDR2 comprising the sequence set forth in SEQ ID NO:3, and a heavy chain variable region comprising a CDR2 comprising the sequence set forth in SEQ ID NO:

9.

15. The therapeutic agent of claim 14, wherein the anti-CTLA-4 antibody comprises a light chain variable region comprising the sequence set forth in SEQ ID NO: 12 and a heavy chain variable region comprising the sequence set forth in SEQ ID NO:

16.

16. The method of claim 15, wherein the anti-CTLA-4 antibody comprises a light chain comprising the sequence set forth in SEQ ID NO:23 and a heavy chain comprising the sequence set forth in SEQ ID NO:

21.

17. The therapeutic agent according to any one of claims 1 to 3, wherein the subject has cancer.

18. The method of claim 17, wherein the cancer is a solid tumor.

19. The method of claim 18, wherein the cancer is advanced or metastatic.

20. The method of claim 17, wherein the subject has previously failed standard treatment for the cancer or has shown intolerance to standard treatment for the cancer.

21. The method of claim 20, wherein the cancer is resistant or refractory to anti-PD-1 / PD-L1 therapy.

22. The therapeutic agent according to any one of claims 1 to 3, wherein the cancer is selected from the group consisting of melanoma, metastatic melanoma, PD(L)-1 resistant melanoma, non-small cell lung adenocarcinoma, metastatic NSCLC, NSCLC with a driver mutation (e.g., EGFR / ALK mutation or other targetable mutation), PD-1 resistant NSCLC, head and neck cancer, adenoid cystic carcinoma (which may be R / M), squamous cell carcinoma, triple-negative (basal cell type) breast cancer, pancreatic cancer, renal cell carcinoma, cervical cancer, endometrial cancer, colon cancer, hepatocellular carcinoma, other solid tumors, and metastatic colorectal cancer (which may have microsatellite instability).

23. (a) anti-CTLA-4 antibody, (b) histidine buffer; (c) α,α-trehalose dihydrate, and (d) Polysorbate 80 and a pH in the range of 5.5 to 6.

5.

24. The composition of claim 23, comprising 1 mg / mL to 100 mg / mL of the anti-CTLA-4 antibody, wherein the composition may contain 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 50 mg / mL or 100 mg / mL of the anti-CTLA-4 antibody, or may contain 5 mg / mL of the anti-CTLA-4 antibody.

25. The composition of claim 23 or claim 24, comprising 5 mM to 40 mM of the histidine buffer, wherein the composition may comprise 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, or 40 mM of the histidine buffer, or may comprise 20 mM of the histidine buffer.

26. 25. The composition of claim 23 or claim 24, comprising 7.0% (w / v) to 10.0% (w / v) of the α,α-trehalose dihydrate, wherein the composition contains the α,α-trehalose dihydrate in the following amounts: 7.0% (w / v), 7.1% (w / v), 7.2% (w / v), 7.3% (w / v), 7.4% (w / v), 7.5% (w / v), 7.6% (w / v), 7.7% (w / v), 7.8% (w / v), 7.9% (w / v), 8.0% (w / v), 8.1% (w / v), 8.2% (w / v), 8. The α,α-trehalose dihydrate may be present in an amount of 3% (w / v), 8.4% (w / v), 8.5% (w / v), 8.6% (w / v), 8.7% (w / v), 8.8% (w / v), 8.9% (w / v), 9.0% (w / v), 9.1% (w / v), 9.2% (w / v), 9.3% (w / v), 9.4% (w / v), 9.5% (w / v), 9.6% (w / v), 9.7% (w / v), 9.8% (w / v), 9.9% (w / v), or 10.0% (w / v), and may contain 8.8% (w / v) of the α,α-trehalose dihydrate.

27. The composition of claim 23 or claim 24, comprising 0.01% (w / v) to 0.10% (w / v) of the polysorbate 80, wherein the composition may comprise 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v) or 0.10% (w / v) of the polysorbate 80, and may comprise 0.06% (w / v) of the polysorbate 80.

28. A composition described in claim 23 or claim 24, having a pH of 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4 or 6.5, wherein the composition may have a pH of 6.0.

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