Combination therapy comprising Anti-CTLA4 antibodies and Anti-PD-1 antibodies for platinum-resistant ovarian cancer treatment

Abstract

The present invention relates to methods for treating platinum-resistant ovarian cancer in a subject using a combination of an anti-CTLA4 antibody and an anti-PD-1 antibody.

Description

[0001] COMBINATION THERAPY COMPRISING ANTI-CTLA4 ANTIBODIES AND

[0002] ANTI-PD-1 ANTIBODIES FOR PLATINUM-RESISTANT OVARIAN CANCER

[0003] TREATMENT

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to methods for treating platinum-resistant ovarian cancer in a subject using a combination of an anti-CTLA4 antibody and an anti-PD-1 antibody.

[0006] BACKGROUND OF THE INVENTION

[0007] Global incidence of ovarian cancer is estimated to be around 300,000 per year. Platinumbased chemotherapy is a standard treatment for advanced ovarian cancer. Drugs targeting DNA repair (PARPi) and those that target vascular endothelial growth factor (VEGF), have been used for maintenance therapy after a platinum response is achieved. While 15-20% of patients remain cancer-free at 3 years after platinum-based therapy, most of the patients either relapse within 3 years or exhibit primary resistance to the treatment. The major focus in drug development for ovarian cancer is to treat patients with platinum-resistant cancer. For a subset of those patients that over-express folate receptor (FR), a single arm pivotal trial (the SORAYA study) has shown promising results, with an objective response rate of 32% and 7.8 months of duration of response.

[0008] Immune checkpoints play a pivotal role in the regulation of the immune response in tumor microenvironments. Immune checkpoints act as gatekeepers of the immune system modulating the nature, magnitude, and duration of the immune response and maintaining self-tolerance. The discovery of immune checkpoint proteins such as Programmed cell death 1 (PD-1) / , Programmed death ligand 1 (PD-L1), and Cytotoxic T lymphocyte antigen-4 (CTLA4) represents a breakthrough in the field of cancer immunotherapy.

[0009] 1

[0010] BNT ref. [P1955WO01] / / C&F ref. 241010WO CTLA4, is also known as CD 152 (cluster of differentiation 152). The interaction between the B7.1 (CD80) (Freeman et al., J Immunol 1989, 143(8): 2714-22) and B7.2 (CD86) (Freeman et al., Science 1993, 262(5135): 909-11; Hathcock et al., Science 1993, 262(5135): 905-7; Wu et al., J Exp Med 1993, 178(5): 1789-93) ligands of antigen presenting cells and the CD28 and CTLA4 receptors (Leach et al., Science 1996, 271(5256): 1734-6; Linsley et al, J Exp Med 1991, 174(3): 561-9; Linsley et al., Proc Natl Acad Sci U S A 1990, 87(13): 5031-5) of T cells governs the activation or downregulation of T cells. CTLA4 is recognized as a key regulator of the adaptive immune response, having a central role in the maintenance of peripheral tolerance and in shaping the repertoire of emerging T cell responses and, is therefore a therapeutic target for the treatment of cancer and inflammation.

[0011] Unlike most cancer types, checkpoint inhibitors have not been approved for the treatment of ovarian cancers. The activity of single agent anti-PD-1 or anti-PD-Ll antibodies had modest objective response rates ranging from 8% to 10%, with median progression-free survival (PFS) times just over 2 months. Limited studies have demonstrated some therapeutic efficacy with the combination of the anti-CTLA4 antibody, ipilimumab, and the anti-PD-1 antibody, nivolumab, when compared with nivolumab alone among ovarian cancer patients who have progressed within 12 months following platinum -based chemotherapy. The Phase 2 study of 100 patients, receiving either nivolumab or nivolumab plus ipilimumab (1 : 1), demonstrated an ORR of 12% in the nivolumab group and 31% in the ipilimumab / nivolumab group.

[0012] Anti-CTLA4 monoclonal antibodies (mAbs) such as the approved antibody, ipilimumab (marketed as YERVOY® by Bristol Myers Squibb), have demonstrated strong and broad cancer immunotherapeutic effects (CITE) in a variety of preclinical models and ipilimumab is used clinically both as monotherapy and as part of combination therapy with nivolumab (anti-PD-1 antibody, marketed as OPDIVO® by Bristol Myers Squibb). However, anti- CTLA4 antibody monotherapy, in the case of ipilimumab, has more immunotherapy-related adverse effects (irAEs) than drugs targeting the checkpoint inhibitor PD-1, such as anti-PD- (L)l therapy. The strong irAEs further limit the doses tolerated by cancer patients. Nevertheless, anti-CTLA4 antibodies can induce long-lasting immunity in cancer patients.

[0013] BNT ref. [P1955WO01] / / C&F ref. [241010WO] Therefore, CTLA4 remains an important immunotherapy target, but major challenges remain in improving both safety and efficacy of anti-CTLA4 antibodies for unmet medical needs.

[0014] Therefore, there is an unmet medical need for improved platinum-resistant ovarian cancer immunotherapeutic methods and new and improved platinum-resistant ovarian cancer therapies addressing the challenges posed by, e.g., autoimmune side effects, and resistance to treatment with immune checkpoint inhibitors.

[0015] SUMMARY OF THE INVENTION

[0016] Against the aforementioned background, it is therefore an object of the present invention to provide safe and effective immunotherapeutic treatment options for subjects afflicted with platinum-resistant ovarian cancer. It is a further object of the present invention to provide effective therapeutic means for the treatment of platinum-resistant ovarian cancer with reduced autoimmune side effects.

[0017] These objects are achieved by the invention set forth in the claims and embodiments explained in more detail below.

[0018] The invention concerns an anti-CTLA4 antibody for use in a method of treating platinum- resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a. the anti-CTLA4 antibody; and b. an anti -PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0019] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3)

[0020] BNT ref. [P1955WO01] / / C&F ref. [241010WO] comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0021] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0022] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0023] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0024] Challenges of cancer immunotherapy with immune checkpoint inhibitors are the undesired side effects associated with the treatment, such as immune-related adverse events and the resistance of patients to the treatment. In the research underlying the invention, the

[0025] BNT ref. [P1955WO01] / / C&F ref. [241010WO] applicants surprisingly found that the combined use of the anti-CTLA4 antibody and the anti-PD-1 antibody provided an unexpected beneficial effect in the treatment of platinum- resistant ovarian cancer, while in parallel providing a safe treatment.

[0026] This surprising effect results in longer overall survival, longer progression-free survival, longer freedom from disease progression (stable disease state), reduction of tumor-related symptoms, and / or reduction of need for pain medications during and / or following the anticancer therapy (anti-CTLA4 antibody and the anti-PD-1 antibody combination therapy). The effect can be reflected in an improved quality of life, such as mobility, strength of appetite, and / or psychological status.

[0027] The invention further provides an anti-CTLA4 antibody and an anti-PD-1 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) the anti-PD-1 antibody. wherein the anti-CTLA4 antibody comprises:

[0028] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0029] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6;

[0030] BNT ref. [P1955WO01] / / C&F ref. [241010WO] wherein the anti-PD-1 antibody comprises:

[0031] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0032] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0033] The invention also concerns a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) an anti-CTLA4 antibody; and b) an anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0034] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0035] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0036] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0037] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0038] The invention also concerns a composition comprising an anti-CTLA4 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) an anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0039] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0040] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0041] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0042] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0043] BNT ref. [P1955WO01] / / C&F ref. [241010WO] The invention also concerns a composition comprising an anti-PD-1 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) an anti-CTLA4 antibody; and b) the anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0044] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0045] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0046] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0047] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0048] Advantageous embodiments of the invention are indicated in the dependent claims and in the following.

[0049] DETAILED DESCRIPTION

[0050] Although certain embodiments of the present invention are described in detail below, it is to be understood that this invention is not limited to the particular embodiments, methodologies, protocols and reagents described herein as these may vary within the scope set by the claims. It is also to be understood that terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which is defined by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0051] In the following description, certain elements of the present invention will be described. These elements may be discussed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples, features and particular embodiments should not be construed to limit the present invention to only the explicitly described embodiments or to the explicitly described combination of features. This description should be understood to disclose and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this

[0052] BNT ref. [P1955WO01] / / C&F ref. [241010WO] application should be considered disclosed by this description unless the context indicates otherwise.

[0053] The above objects are achieved by the following embodiments in accordance with the invention:

[0054] 1. An anti-CTLA4 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) an anti -PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0055] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0056] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0057] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0058] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0059] 2. An anti-PD-1 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-PD-1 antibody; and b) an anti-CTLA4 antibody, wherein the anti-CTLA4 antibody comprises:

[0060] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0061] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0062] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0063] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0064] 3. The anti-CTLA4 antibody for use according to embodiment 1 or the anti-PD-1 antibody for use according to embodiment 2, wherein the anti-CTLA4 antibody and the anti-PD-1 antibody are administered separately.

[0065] 4. The anti-CTLA4 antibody for use according to embodiment 1 or 3 or the anti-PD-1 antibody for use according to embodiment 2 or 3, wherein the anti-CTLA4 antibody and the anti-PD-1 antibody are administered concurrently or consecutively, optionally wherein the anti-CTLA4 antibody and the anti-PD-1 antibody are administered consecutively.

[0066] BNT ref. [P1955WO01] / / C&F ref. [241010WO] 5. The anti-CTLA4 antibody for use according to embodiments 1, 3 or 4 or the anti- PD-1 antibody for use according to embodiments 2-4, wherein the anti-CTLA4 antibody and the anti-PD-1 antibody are administered intravenously.

[0067] 6. The anti-CTLA4 antibody for use according to embodiments 1 or 3-5 or the anti- PD-1 antibody for use according to embodiments 2-5, wherein the anti-CTLA4 antibody and the anti-PD-1 antibody are administered via an intravenous injection or an intravenous infusion, optionally an intravenous infusion.

[0068] 7. The anti-CTLA4 antibody for use according to embodiments 1 or 3-6 or the anti- PD-1 antibody for use according to embodiments 2-6, wherein the anti-CTLA4 antibody dosage administered ranges from about 0.1 mg / kg to about 2.9 mg / kg body weight, optionally from about 0.5 mg / kg to about 2.9 mg / kg body weight, optionally from about 0.5 mg / kg to about 2.5 mg / kg body weight, optionally from about 1 mg / kg to about 2 mg / kg body weight.

[0069] 8. The anti-CTLA4 antibody for use according to embodiments 1 or 3-7 or the anti- PD-1 antibody for use according to embodiments 3-7, wherein the anti-CTLA4 antibody dosage administered is independently selected from about 0.1 mg / kg body weight, about 0.3 mg / kg body weight, about 0.5 mg / kg body weight, about 1 mg / kg body weight, about 1.5 mg / kg body weight, about 2 mg / kg body weight, about 2.5 mg / kg body weight, and about 2.9 mg / kg body weight, optionally wherein the anti- CTLA4 antibody dosage administered is independently selected from about 1 mg / kg body weight and about 2 mg / kg body weight.

[0070] 9. The anti-CTLA4 antibody for use according to embodiments 1 or 3-8 or the anti- PD-1 antibody for use according to embodiments 2-8, wherein the anti-PD-1 antibody dosage administered ranges from about 175 to about 225 mg.

[0071] 10. The anti-CTLA4 antibody for use according to embodiments 1 or 3-9 or the anti- PD-1 antibody for use according to embodiments 2-9, wherein the anti-PD-1 antibody dosage administered is about 200 mg.

[0072] BNT ref. [P1955WO01] / / C&F ref. [241010WO] The anti-CTLA4 antibody for use according to embodiments 1 or 3-10 or the anti- PD-1 antibody for use according to embodiments 2-10, wherein a treatment cycle is repeated at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 times, optionally at least 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33 or 35 times. The anti-CTLA4 antibody for use according to embodiments 1 or 3-11 or the anti- PD-1 antibody for use according to embodiments 2-11, wherein each treatment cycle has up to about 18 to about 28 days, optionally about 18 to about 24 days. The anti-CTLA4 antibody for use according to embodiments 1 or 3-12 or the anti- PD-1 antibody for use according to embodiments 2-12, wherein the anti-CTLA4 antibody is administered about every 4 weeks, optionally about every 3 weeks. The anti-CTLA4 antibody for use according to embodiments 1 or 3-13 or the anti- PD-1 antibody for use according to embodiments 2-13, wherein the anti-PD-1 antibody is administered about every 4 weeks, optionally about every 3 weeks. The anti-CTLA4 antibody for use according to embodiments 1 or 3-14 or the anti- PD-1 antibody for use according to embodiments 2-14, wherein the anti-CTLA4 antibody and / or the anti-PD-1 antibody are administered for 17 to 35 treatment cycles or up to 1 to 2 years, optionally 35 treatment cycles or up to 2 years. The anti-CTLA4 antibody for use according to embodiments 1 or 3-15 or the anti- PD-1 antibody for use according to embodiments 2-15, wherein the anti-CTLA4 antibody and / or the anti-PD-1 antibody are formulated with one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The anti-CTLA4 antibody for use according to embodiments 1 or 3-16 or the anti- PD-1 antibody for use according to embodiments 2-16, wherein the subject has been previously treated for cancer, optionally wherein the subject had at least one previous chemotherapy treatment.

[0073] BNT ref. [P1955WO01] / / C&F ref. [241010WO] 18. The anti-CTLA4 antibody or the anti-PD-1 antibody for use according to embodiment 17, wherein the at least one previous chemotherapy treatment comprises or is a platinum-containing chemotherapy treatment.

[0074] 19. The anti-CTLA4 antibody for use according to embodiments 1 or 3-18 or the anti- PD-1 antibody for use according to embodiments 2-18, wherein the subject has been previously treated with bevacizumab.

[0075] 20. The anti-CTLA4 antibody for use according to embodiments 1 or 3-19 or the anti- PD-1 antibody for use according to embodiments 2-19, wherein overall survival is increased in said subject compared to the anti-PD-1 antibody, preferably pembrolizumab, treatment alone.

[0076] 21. The anti-CTLA4 antibody for use according to embodiments 1 or 3-20 or the anti- PD-1 antibody for use according to embodiments 2-20, wherein median progression-free survival is increased in said subject compared to the anti-PD-1 antibody, preferably pembrolizumab, treatment alone.

[0077] 22. The anti-CTLA4 antibody for use according to embodiments 1 or 3-21 or the anti- PD-1 antibody for use according to embodiments 2-21, wherein the platinum- resistant ovarian cancer is selected from high-grade serous ovarian cancer, primary peritoneal cancer, and fallopian tube cancer.

[0078] 23. The anti-CTLA4 antibody for use according to embodiments 1, 3-22 or the anti-PD- 1 antibody for use according to embodiments 2-22, wherein the platinum-containing chemotherapy comprises or is selected from satraplatin, cisplatin, carboplatin, nedaplatin, lobaplatin or combinations thereof.

[0079] 24. The anti-CTLA4 antibody for use according to embodiments 1, 3-23 or the anti-PD- 1 antibody for use according to embodiments 2-23, wherein the platinum-containing chemotherapy comprises a further chemotherapeutic agent, optionally wherein the further chemotherapeutic agent is paclitaxel or docetaxel.

[0080] BNT ref. [P1955WO01] / / C&F ref. [241010WO] The anti-CTLA4 antibody for use according to embodiments 1 or 3-18, 21-24 or the anti-PD-1 antibody for use according to embodiments 2-18, 20-24, wherein the subject has previously not been treated with bevacizumab. The anti-CTLA4 antibody for use according to embodiments 1 or 3-25 or the anti- PD-1 antibody for use according to embodiments 2-25, wherein the anti-CTLA4 antibody comprises: a) a heavy chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 7; and b) a light chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 8, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 8. The anti-CTLA4 antibody for use according to embodiments 1 or 3-26 or the anti- PD-1 antibody for use according to embodiments 2-26, wherein the anti-CTLA4 antibody comprises an IgGl Fc, preferably comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 9 or an amino acid sequence comprising at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9. The anti-CTLA4 antibody for use according to embodiments 1, 3-27 or the anti-PD- 1 antibody for use according to embodiments 2-27, wherein the anti-CTLA4 antibody comprises: a) a heavy chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 10, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10; and

[0081] BNT ref. [P1955WO01] / / C&F ref. [241010WO] b) a light chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 12 or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 12. The anti-CTLA4 antibody for use according to embodiments 1, 3-28 or the anti-PD- 1 antibody for use according to embodiments 2-28, wherein the anti-CTLA4 antibody is capable of binding to human CTLA4. The anti-CTLA4 antibody for use according to embodiments 1, 3-29 or the anti-PD- 1 antibody for use according to embodiments 2-29, wherein the anti-CTLA4 antibody is a humanized anti-CTLA4 antibody. The anti-CTLA4 antibody for use according to embodiments 1, 3-30 or the anti-PD- 1 antibody for use according to embodiments 2-30, wherein the subject is a human. The anti-CTLA4 antibody for use according to embodiments 1, 3-31 or the anti-PD- 1 antibody for use according to embodiments 2-31, wherein the anti-CTLA4 antibody and / or the anti-PD-1 antibody are administered on the first day of each treatment cycle. The anti-CTLA4 antibody for use according to embodiments 1, 3-32 or the anti-PD- 1 antibody for use according to embodiments 2-32, wherein the anti-PD-1 antibody comprises: a) a heavy chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 21 or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 21; and b) a light chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 22, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 22.

[0082] BNT ref. [P1955WO01] / / C&F ref. [241010WO] 34. The anti-CTLA4 antibody for use according to embodiments 1, 3-33 or the anti-PD-

[0083] 1 antibody for use according to embodiments 2-33, wherein the anti-PD-1 antibody comprises: a) a heavy chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 23, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 23; and b) a light chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 24 or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 24.

[0084] 35. The anti-CTLA4 antibody for use according to embodiments 1, 3-34 or the anti-PD- 1 antibody for use according to embodiments 2-34, wherein the anti-PD-1 antibody is pembrolizumab.

[0085] 36. An anti-CTLA4 antibody and an anti-PD-1 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) the anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0086] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0087] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0088] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0089] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0090] 37. A method of treating platinum -resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) an anti-CTLA4 antibody; and b) an anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0091] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0092] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0093] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0094] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0095] BNT ref. [P1955WO01] / / C&F ref. [241010WO] 38. A composition comprising an anti-CTLA4 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) an anti -PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0096] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0097] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0098] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0099] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0100] 39. The composition of embodiment 38, wherein the anti-CTLA-4 antibody has been diluted with 5% Dextrose Solution to a final concentration of about 0.5 to about 3.0 mg / mL, from a formulation containing 30 mg / mL anti-CTLA-4 antibody, 20 mM histidine buffer, 8.8% (w / v) trehalose dihydrate, and 0.06% (w / v) PS80 at pH 6.0.

[0101] 40. A composition comprising an anti-PD-1 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) an anti-CTLA4 antibody; and b) the anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0102] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0103] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2)

[0104] BNT ref. [P1955WO01] / / C&F ref. [241010WO] comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0105] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0106] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0107] 41. The composition according to any of embodiments 38-40, wherein the composition is a pharmaceutical composition.

[0108] 42. The composition according to any of embodiments 38-41, wherein the composition comprises one or more pharmaceutically acceptable carriers, diluents and / or excipients.

[0109] Definitions

[0110] The terms indicated for explanation of the invention have the following meaning, unless otherwise indicated in the description or the embodiments. Additional definitions are set forth throughout the detailed description.

[0111] BNT ref. [P1955WO01] / / C&F ref. [241010WO] Terms “a” and “an” and “the” and similar reference used in the context of describing the invention (especially in the context of the embodiments) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0112] The terms “about” or “approximately” as used herein denotes a range of ±10% of a reference value. For examples, “about 10” defines a range of 9 to 11. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” or “approximately” in that context.

[0113] The term “administration route” refers to the means of administration of an active agent or a pharmaceutical composition. The terms “active agent” or “therapeutically effective agent” as used herein refer to compounds that exert a pharmaceutical effect in the treatment of a disease. The anti-CTLA4 antibody and the anti-PD-1 antibody as disclosed herein can be administered by any administration route known to the skilled person. In general, active agents or pharmaceutical compositions can be administered using any suitable enteral route or parenteral route of administration. The term “enteral route” of administration refers to the administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal route, or intragastric route. “Parenteral route” of administration refers to a route of administration other than enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumor, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal, subcutaneous, or topical administration. For example, anti-CTLA4 antibody and the anti-PD-1 antibody (such as pembrolizumab) of the present disclosure can be administered using different enteral or parenteral administration routes. The anti-CTLA4 antibody and the anti-PD-1 antibody of the present disclosure can also be administered using the same administration route, e.g., intravenous administration using an intravenous injection or intravenous infusion.

[0114] Unless expressly specified otherwise, the term “comprising” is used in the context of the present disclosure to indicate that further members may optionally be present in addition to

[0115] BNT ref. [P1955WO01] / / C&F ref. [241010WO] the members of the list introduced by “comprising”. It is, however, contemplated as specific embodiments of the present invention that each time the term “comprising” is used, this shall also encompass the possibility of no further members being present, i.e., for the purpose of this embodiment “comprising” can be understood as having the meaning of “consisting of’.

[0116] The terms “concurrent administration” or “co-administration” as used herein refer to the administration of at least two active agents, therapeutically effective agents, or pharmaceutical compositions which are administered simultaneously or essentially at the same time. “Essentially at the same time” as used herein means within about 1 minute, about 5 minutes, about 10 minutes, or about 15 minutes period of each other. For example, the anti-CTLA4 antibody and the anti-PD-1 antibody of the present disclosure can be administered essentially at the same time using two different pharmaceutical compositions, each individually comprising the anti-CTLA4 antibody or the anti-PD-1 antibody disclosed herein.

[0117] The term “consecutive administration” as used herein refers to the sequential administration of active agents, therapeutically effective agents, or pharmaceutical compositions in treatment cycles. The term consecutive administration includes the sequential administration of the same or of different, i.e., at least two, active agents, therapeutically effective agents, or pharmaceutical compositions.

[0118] Preferably, the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, H.G.W. Leuenberger, B. Nagel, and H. K51bl, Eds., (1995) Helvetica Chimica Acta, CH-4010 Basel, Switzerland.

[0119] The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of biochemistry, cell biology, immunology, and recombinant DNA techniques which are explained in the literature in the field (cf., e.g., Molecular Cloning: A Laboratory Manual, 4th Edition, M.R. Green, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 2012).

[0120] BNT ref. [P1955WO01] / / C&F ref. [241010WO] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0121] Herein, the term “DNA” relates to a nucleic acid molecule which is entirely or at least substantially composed of deoxyribonucleotide residues. In preferred embodiments, the DNA contains all or a majority of deoxyribonucleotide residues. As used herein, “deoxyribonucleotide” refers to a nucleotide which lacks a hydroxyl group at the 2’- position of a P-D-ribofuranosyl group. DNA encompasses without limitation, double stranded DNA, single stranded DNA, isolated DNA such as partially purified DNA, essentially pure DNA, synthetic DNA, recombinantly produced DNA, as well as modified DNA that differs from naturally occurring DNA by the addition, deletion, substitution and / or alteration of one or more nucleotides. Such alterations may refer to addition of nonnucleotide material to internal DNA nucleotides or to the end(s) of DNA. It is also contemplated herein that nucleotides in DNA may be non-standard nucleotides, such as chemically synthesized nucleotides or ribonucleotides.

[0122] As used herein, the term “encode” or “encoding” refers to sequence information of a first molecule that guides production of a second molecule having a defined sequence of nucleotides (e.g., mRNA) or a defined sequence of amino acids. For example, a DNA molecule can encode an RNA molecule (e.g., by a transcription process that includes a DNA-dependent RNA polymerase enzyme). An RNA molecule can encode a polypeptide (e.g., by a translation process). Thus, a gene, a cDNA, or a single-stranded RNA (e.g., an mRNA) encodes a polypeptide if transcription and translation of mRNA corresponding to that gene produces the polypeptide in a cell or other biological system. In some embodiments, a coding region of a single-stranded RNA encoding a target polypeptide agent refers to a coding strand, the nucleotide sequence of which is identical to the mRNA sequence of such a target polypeptide agent. In some embodiments, a coding region of a single-stranded RNA encoding a target polypeptide agent refers to a non-coding strand of

[0123] BNT ref. [P1955WO01] / / C&F ref. [241010WO] such a target polypeptide agent, which may be used as a template for transcription of a gene or cDNA. As is understood in the art, the phrase “nucleic acid encoding a peptide or protein” means that the nucleic acid, if present in the appropriate environment, for example within a cell and / or in a cell-free translation system, can direct the assembly of amino acids to produce the peptide or protein via a process of translation.

[0124] The term “in vitro transcription” or “IVT” means that the transcription (i.e., the generation of RNA) is conducted in a cell-free manner. I.e., IVT does not use living / cultured cells but rather the transcription machinery extracted from cells (e.g., cell lysates or the isolated components thereof, including an RNA polymerase (preferably T7, T3 or SP6 polymerase)).

[0125] The terms “identity” or “sequence identity” refer to the overall relatedness between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or polypeptide molecules. “Sequence identity” between two nucleic acid sequences indicates the percentage of nucleotides that are identical between the sequences. The terms “% identical”, “% identity” or similar terms refer to the percentage of nucleotides or amino acids which are identical in an optimal alignment between the sequences to be compared. Said percentage is purely statistical, and the differences between the two sequences may be but are not necessarily randomly distributed over the entire length of the sequences to be compared. Comparisons of two sequences are usually carried out by comparing the sequences, after optimal alignment, with respect to a segment or “window of comparison”, in order to identify local regions of corresponding sequences. The optimal alignment for a comparison may be carried out manually or with the aid of the local homology algorithm by Smith and Waterman, 1981, Ads App. Math. 2, 482, with the aid of the local homology algorithm by Needleman and Wunsch, 1970, J. Mol. Biol. 48, 443, with the aid of the similarity search algorithm by Pearson and Lipman, 1988, Proc. Natl Acad. Sei. USA 88, 2444, or with the aid of computer programs using said algorithms (GAP, BESTFIT, FASTA, BLASTP, BLASTN and TFASTA in Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.). For example, percent identity of two sequences is determined using the BLASTN or BLASTP algorithm, as available on the United States National Center for Biotechnology Information (NCBI)

[0126] BNT ref. [P1955WO01] / / C&F ref. [241010WO] website (e.g., at the website blast.ncbi.nlm.nih.gov / Blast.cgi?PAGE_TYPE=BlastSearch&BLAST _SPEC=blast2seq&LINK_LOC=align2seq). The algorithm parameters used for BLASTN algorithm on the NCBI website may include: (i) Expect Threshold set to 10; (ii) Word Size set to 28; (iii) Max matches in a query range set to O; (iv) Match / Mismatch Scores set to 1, -2; (v) Gap Costs set to Linear; and (vi) the filter for low complexity regions being used. The algorithm parameters used for BLASTP algorithm on the NCBI website may include: (i) Expect Threshold set to 10; (ii) Word Size set to 3; (iii) Max matches in a query range set to O; (iv) Matrixset to BLOSUM62; (v) Gap Costs set to Existence: 11 Extension: 1; and (vi) conditional compositional score matrix adjustment. Percentage identity is obtained by determining the number of identical positions at which the sequences to be compared correspond, dividing this number by the number of positions compared (e.g., the number of positions in the reference sequence) and multiplying this result by 100. In some embodiments, the degree of identity is given for a region which is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% of the entire length of the reference sequence. For example, if the reference nucleic acid or amino acid sequence consists of 200 nucleotides or amino acids, the degree of identity is given for at least about 20, at least about 40, at least about 60, at least about 80, at least about 100, at least about 120, at least about 140, at least about 160, at least about 180, or about 200 nucleotides or amino acids, in some embodiments in continuous nucleotides or amino acids. In some embodiments, the degree of identity is given for the entire length of the reference sequence. Nucleic acid sequences or amino acid sequences having a particular degree of identity to a given nucleic acid sequence or amino acid sequence, respectively, may have at least one functional property of said given sequence, e.g., and in some instances, are functionally equivalent to said given sequence. One important property includes an immunogenic property, in particular when administered to a subject. In some embodiments, a nucleic acid sequence or amino acid sequence having a particular degree of identity to a given nucleic acid sequence or amino acid sequence is functionally equivalent to the given sequence.

[0127] BNT ref. [P1955WO01] / / C&F ref. [241010WO] The term “gene” refers to a DNA sequence in a chromosome that codes for a protein. In some embodiments, a gene includes coding sequence (i.e., sequence that encodes a particular protein); in some embodiments, a gene includes non-coding sequence. In some particular embodiments, a gene may include both coding (e.g., exonic) and non-coding (e.g., intronic) sequences. In some embodiments, a gene may include one or more regulatory elements that, for example, may control or impact one or more aspects of gene expression (e.g., cell-type- specific expression, inducible expression, etc.).

[0128] The term “carrier” refers to a component which may be natural, synthetic, organic, inorganic in which the active ingredients of the disclosure are combined in order to facilitate, enhance or enable administration of the anti-CTLA4 antibody and / or the anti-PD- 1 antibody. A carrier as used herein may be one or more compatible solid or liquid fillers, diluents or encapsulating substances, which are suitable for administration to the subject. Suitable carriers include, without limitation, sterile water, Ringer, Ringer lactate, sterile sodium chloride solution, isotonic saline, polyalkylene glycols, hydrogenated naphthalenes and, in particular, biocompatible lactide polymers, lactide / glycolide copolymers or polyoxyethylene / polyoxy-propylene copolymers. Pharmaceutically acceptable carriers, excipients or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R Gennaro edit. 1985). Pharmaceutical carriers, excipients or diluents can be selected with regard to the intended route of administration and standard pharmaceutical practice.

[0129] The term “excipient” is a substance which may be present in a formulation of the anti- CTLA4 antibody and / or the anti-PD-1 antibody but is not an active ingredient. Examples of excipients include, without limitation, carriers, binders, diluents, lubricants, thickeners, surface active agents, preservatives, stabilizers, emulsifiers, buffers, flavoring agents, or colorants.

[0130] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means solvents, dispersion media, coatings, antibacterial agents and antifungal agents, isotonic agents, and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically

[0131] BNT ref. [P1955WO01] / / C&F ref. [241010WO] active substances is well known in the art. In certain embodiments, the pharmaceutically acceptable carrier or excipient is not naturally occurring. The term “pharmaceutically acceptable” refers to the non-toxicity of a material which does not interact with the action of the active component of the pharmaceutical composition.

[0132] The term “diluent” relates to a diluting and / or thinning agent. Moreover, the term “diluent” includes any one or more of fluid, liquid or solid suspension and / or mixing media. Nonlimiting examples of suitable diluents include ethanol, glycerol, and water.

[0133] The term “subject” relates to a female human. The subject may be of any age. The subject is a subject having cancer, in particular a female subject having platinum-resistant ovarian cancer. The subject can be a patient.

[0134] The term “treating” when used in the context of a disease or disease condition means ameliorating, improving or remedying a disease, disorder, or symptom of a disease or condition associated with the disease, or can mean completely or partially stopping, on a molecular level, the biochemical basis of the disease. It describes an act that leads to the elimination, reduction, alleviation, reversal, or prevention or delay of onset or recurrence of any symptom of a disease.

[0135] The term “pharmaceutical composition” relates to a composition comprising an active agent or a therapeutically effective agent, preferably together with pharmaceutically acceptable carriers, diluents and / or excipients. Said pharmaceutical composition is useful for treating, preventing, or reducing the severity of a disease by administration of said pharmaceutical composition to a subject. For example, a pharmaceutical composition can comprise the anti-CTLA4-antibody and / or the anti-PD-1 antibody disclosed herein.

[0136] The term “cancer” refers to a neoplasm or tumor resulting from abnormal uncontrolled growth of cells. The term “tumor” as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas.

[0137] BNT ref. [P1955WO01] / / C&F ref. [241010WO] Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0138] The term “CTLA4” or “CTLA-4” relates to cytotoxic T lymphocyte antigen-4. “CTLA4” or “CTLA-4” are used interchangeably herein. CTLA4 is expressed on the surface of cells and, if it is located at the surface of said cells, is accessible to binding by CTLA4 specific antibodies. “Cell surface” is used in accordance with its normal meaning in the art, and thus includes the outside of the cell which is accessible to binding by proteins and other molecules. For example, a transmembrane protein having one or more extracellular portions is considered as being expressed on the cell surface.

[0139] The term “immune cell” means any cell of hematopoietic lineage involved in regulating an immune response against an antigen (e.g., a bacterial or viral infection or an auto-antigen). In some embodiments, an immune cell is a leukocyte, such as a white blood cell. Immune cells include neutrophils, eosinophils, basophils, lymphocytes, and / or monocytes. Lymphocytes include T lymphocytes (T cells) and B lymphocytes (B cells). Immune cells can also be dendritic cells, natural killer (NK) cells, and / or a mast cell.

[0140] The term “antibody” refers to a molecule that possesses an antigen-binding site. The term encompasses functional antibody fragments or antigen-binding fragments, such as a Fab, a Fab’, a F(ab’)2, a scFV, a rlgG, a diabody, a triabody, a minibody and a single-domain antibody (sdAB). The antibody can comprise a “variable region”. The terms “variable region” and “variable domain” are used interchangeably herein. The term “variable region” is intended to distinguish such domain of the immunoglobulin from domains that are broadly shared by antibodies (such as an antibody Fc region). The variable region comprises a “hypervariable region” whose residues are responsible for antigen binding, and as used herein means the segment of an antibody which contains three CDRs, designated CDR1, CDR2 and CDR3. A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain may be referred to as “VH.” The

[0141] BNT ref. [P1955WO01] / / C&F ref. [241010WO] variable region of the light chain may be referred to as “VL.” Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, the CDRs, which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C-terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR” (i.e., typically at approximately residues 24-34 (LI), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and at approximately residues 27-35 (Hl), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain) and / or those residues from a “hypervariable loop” (i.e., residues 26-32 (LI), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26-32 (Hl), 53-55 (H2) and 96-101 (H3) in the heavy chain variable domain. The variable domains of the heavy and light chains each contain three CDRs, designated CDR1, CDR2 and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, such as the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, Md., 1991; Kabat et al., J Biol Chem 1977, 252: 6609-6616; Kabat, Adv Prot Chem 1978, 32: 1-75), the Chothia numbering system (Chothia & Lesk, J Mol Biol 1987, 196: 901-917; Chothia et al., Nature 1989, 342: 878-883) or the IMGT numbering system (Lefranc et al., Dev Comparat Immunol 2003, 27: 55-77). For a given antibody, those skilled in the art will readily identify the CDRs defined by each numbering system. Also, the correspondence between different numbering systems is well known to those skilled in the art (Lefranc et al., Dev Comparat Immunol 2003, 27: 55-77). “Framework Region” or “FR” residues are those variable domain residues other than the hypervariable region or CDR residues as herein defined. An antibody may comprises or consist of any class of light chain , particularly of, kappa, lambda, or variants thereof. “Antibody” includes monoclonal antibodies, multi-specific antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, camelized antibodies, single chain antibodies, disulfide-linked Fvs (sdFv), intrabodies, and anti -idiotypic (anti-Id) antibodies (including, e.g., anti-Id and anti-anti-Id antibodies to antibodies disclosed herein). In particular, such antibodies include immunoglobulin molecules of any type (e.g.,

[0142] BNT ref. [P1955WO01] / / C&F ref. [241010WO] IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGi, IgG?, IgGs, IgG4, IgAi and IgA2) or subclass.

[0143] The term “antigen-binding fragment” or “antibody-binding portion” of an antibody refers to one or more portions or fragments of an antibody that contain the antibody’s CDRs and optionally the framework residues that comprise the antibody’s variable domain antigen recognition site, and exhibit an ability to immunospecifically bind an antigen. Examples of antibody fragments encompassed within the term “antigen binding fragment” or “antigen binding portion” include (i) Fab fragments, monovalent fragments consisting of the VL, VH, CL and CH domains; (ii) F(ab’)2 fragments, bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) Fd fragments consisting of the VH and CH domains; (iv) Fv fragments consisting of the VL and VH domains of a single arm of an antibody, (v) dAb fragments (Ward et al., 1989, Nature 341 :544-546), which consist of a VH domain; (vi) isolated complementarity determining regions (CDR), and (vii) combinations of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., 1988, Science, 242:423-426; and Huston et al., 1988, Proc. Natl. Acad. Sci. USA, 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding fragment” or “antibody-binding portion” of an antibody. Also included within the term “antigen-binding” fragment of an antibody are a rlgG fragments consisting of one heavy chain (HC) and one light chain (LC), i.e. consisting of one of the identical halves of an IgG antibody. A further example are binding-domain immunoglobulin fusion proteins comprising (i) a binding domain polypeptide that is fused to an immunoglobulin hinge region polypeptide, (ii) an immunoglobulin heavy chain CH2 constant region fused to the hinge region, and (iii) an immunoglobulin heavy chain CH3 constant region fused to the CH2 constant region. The binding domain polypeptide can be a heavy chain variable region or a light chain variable region. Binding-domain immunoglobulin fusion proteins are further disclosed in U.S. Patent Application Publication Nos. 2003 / 0118592 and 2003 / 0133939. These antibody fragments can be

[0144] BNT ref. [P1955WO01] / / C&F ref. [241010WO] obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. “Antigenbinding fragment” or “antibody -binding portion” may further include fusion proteins comprising the antibody’s variable region antigen recognition site and a heterologous protein (e.g., a toxin, an antigen recognition site for a different antigen, an enzyme, a receptor or receptor ligand, etc.). As used within the present invention, the term “fragment” refers to a peptide or polypeptide comprising an amino acid sequence of at least 5 contiguous amino acid residues, at least 10 contiguous amino acid residues, at least 15 contiguous amino acid residues, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 40 contiguous amino acid residues, at least 50 contiguous amino acid residues, at least 60 contiguous amino residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, at least 125 contiguous amino acid residues, at least 150 contiguous amino acid residues, at least 175 contiguous amino acid residues, at least 200 contiguous amino acid residues, or at least 250 contiguous amino acid residues.

[0145] The term “human antibody” refers to an antibody that comprises human immunoglobulin protein sequences only. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” or “rat antibody” refer to an antibody that comprises only mouse or rat immunoglobulin sequences, respectively.

[0146] A “humanized antibody” is an immunoglobulin comprising a human framework region and one or more CDRs from a non-human (usually a mouse or rat) immunoglobulin. The nonhuman immunoglobulin providing the CDRs is called the “donor” and the human immunoglobulin providing the framework is called the “acceptor”. Constant regions need not be present, but if they are, they preferably can be substantially identical to human immunoglobulin constant regions, i.e., at least about 85-90%, preferably about 95% or more identical. Hence, all parts of a humanized immunoglobulin, except possibly the CDRs, are substantially identical to corresponding parts of natural human immunoglobulin sequences. A humanized antibody is an antibody comprising a humanized light chain and a

[0147] BNT ref. [P1955WO01] / / C&F ref. [241010WO] humanized heavy chain immunoglobulin. For example, a humanized antibody would not encompass a typical chimeric antibody, because e.g., the entire variable region of a chimeric antibody is non-human. One says that the donor antibody has been “humanized”, by the process of “humanization”, because the resultant humanized antibody is expected to bind to the same antigen as the donor antibody that provides the CDRs. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which hypervariable region residues of the recipient are replaced by hypervariable region residues from a non-human species (donor antibody) such as mouse, rat, rabbit or a non-human primate having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non- human residues. Furthermore, humanized antibodies may comprise residues which are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin that immunospecifically binds to an Fc.gamma.RIIB polypeptide, that has been altered by the introduction of amino acid residue substitutions, deletions or additions (i.e., mutations).

[0148] An antibody that “specifically binds to” or “immunospecifically binds to” a specified target protein is an antibody that exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives. Antibodies, or binding fragments thereof, useful in the present invention will bind to the target protein with an affinity that is at least two times greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins. As used herein, an antibody is said to bind specifically to a polypeptide comprising a given amino acid

[0149] BNT ref. [P1955WO01] / / C&F ref. [241010WO] sequence, e.g., the amino acid sequence of a mature human CTLA4 molecule, if it binds to polypeptides comprising that sequence but preferably does not bind to proteins lacking that sequence.

[0150] “Chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in an antibody derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in an antibody derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0151] The term “epitope” refers to the part of an antigen that as used herein, refers to an agent that elicits an immune response; and / or an agent that binds to a T cell receptor (e.g., when presented by an MHC molecule) or to an antibody. For example, epitopes are the discrete, three-dimensional sites on an antigen which are recognized by the immune system.

[0152] Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non- conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

[0153] The term “antigen” as used herein refers to an agent that elicits an immune response; and / or an agent that binds to a T cell receptor (e.g., when presented by an MHC molecule) or to an antibody. In some embodiments, an antigen elicits a humoral response (e.g., including production of antigen-specific antibodies); in some embodiments, an antigen elicits a cellular response (e.g., involving T-cells whose receptors specifically interact with the antigen). In some embodiments, an antigen binds to an antibody and may or may not induce a particular physiological response in an organism. In general, an antigen may be or include any chemical entity such as, for example, a small molecule, a nucleic acid, a polypeptide, a carbohydrate, a lipid, a polymer (in some embodiments other than a biologic polymer [e.g., other than a nucleic acid or amino acid polymer]) etc. In some embodiments, an antigen is

[0154] BNT ref. [P1955WO01] / / C&F ref. [241010WO] or comprises a polypeptide. In some embodiments, an antigen is or comprises a glycan. Those of ordinary skill in the art will appreciate that, in general, an antigen may be provided in isolated or pure form, or alternatively may be provided in crude form (e.g., together with other materials, for example in an extract such as a cellular extract or other relatively crude preparation of an antigen-containing source). In some embodiments, antigens utilized in accordance with the present invention are provided in a crude form. In some embodiments, an antigen is a recombinant antigen.

[0155] The terms “chemotherapeutic agent” or “chemotherapeutical agent” or “chemotherapy agent” can be used interchangeably herein. A chemotherapeutic agent is a chemical compound useful in the treatment of cancer. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, anti -estrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing horm one-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, anti-sense oligonucleotides that that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth. Chemotherapeutic agents useful in the treatment methods of the present disclosure include cytostatic and / or cytotoxic agents. Chemotherapeutic agents as used herein do not include antibodies.

[0156] The term “combination therapy” as used herein refers to the anti-CTLA4 antibody and the anti-PD-1 antibody as disclosed herein for use in a method of treating a subject with platinum-resistant ovarian cancer. Each component of the combination therapy can be administered separately, concurrently, or consecutively.

[0157] The term “nucleoside” relates to compounds which can be thought of as nucleotides without a phosphate group. While a nucleoside is a nucleobase linked to a sugar (e.g., ribose or deoxyribose), a nucleotide is composed of a nucleoside and one or more phosphate groups. Examples of nucleosides include cytidine, uridine, pseudouridine, adenosine, and guanosine. The five standard nucleosides which usually make up naturally occurring nucleic acids are uridine, adenosine, thymidine, cytidine and guanosine. The five

[0158] BNT ref. [P1955WO01] / / C&F ref. [241010WO] nucleosides are commonly abbreviated to their one letter codes U, A, T, C and G, respectively. However, thymidine is more commonly written as “dT” (“d” represents “deoxy”) as it contains a 2'-deoxyribofuranose moiety rather than the ribofuranose ring found in uridine. This is because thymidine is found in deoxyribonucleic acid (DNA) and not ribonucleic acid (RNA). Conversely, uridine is found in RNA and not DNA. The remaining three nucleosides may be found in both RNA and DNA. In RNA, they would be represented as A, C and G, whereas in DNA they would be represented as dA, dC and dG. A modified purine (A or G) or pyrimidine (C, T, or U) base moiety is, in some embodiments, modified by one or more alkyl groups, e.g., one or more C1-4 alkyl groups, e.g., one or more methyl groups. Particular examples of modified purine or pyrimidine base moieties include N7-alkyl-guanine, N6-alkyl-adenine, 5-alkyl-cytosine, 5-alkyl-uracil, and N(l)-alkyl-uracil, such as N7-CI-4 alkyl-guanine, N6-CI-4 alkyl-adenine, 5-C1-4 alkylcytosine, 5-C1-4 alkyl-uracil, and N(1)-CI-4 alkyl-uracil, preferably N7-methyl-guanine, N6- methyl-adenine, 5-methyl-cytosine, 5-methyl-uracil, and N(l)-methyl-uracil.

[0159] The term “mRNA” refers to messenger-RNA that comprises a coding sequence encoding a polypeptide. An mRNA may further comprise non-coding sequences such as a 5 ’cap, a 5’UTR, a 3’UTR, a Kozak sequence, an FI element or a poly(A) tail or any combination thereof. According to the present disclosure, the term “mRNA” means “messenger-RNA” and includes a “transcript” which may be generated by using a DNA template. Generally, mRNA encodes a peptide or polypeptide. mRNA is single-stranded but may contain self- complementary sequences that allow parts of the mRNA to fold and pair with itself to form double helices. According to the present disclosure, “dsRNA” means double-stranded RNA and is RNA with two partially or completely complementary strands.

[0160] The term “overall survival” (OS) as used herein refers to the time period between the first treatment of a subject suffering from cancer with an active agent, therapeutically effective agent, or pharmaceutical composition and the death of the subject by any cause. OS as used herein is determined over a period of 48 months.

[0161] The term “platinum-containing chemotherapy” or “platinum-based chemotherapy” refers to the use of chemotherapeutic agent(s) (also known as platins) for treating cancer that are coordination complexes of platinum. Platinum-containing chemotherapeutic agents (also

[0162] BNT ref. [P1955WO01] / / C&F ref. [241010WO] referred to as “platinum” or “platins”) are alkylating agents that crosslink DNA, resulting in ineffective DNA mismatch repair and generally leading to apoptosis. Examples of platins include cisplatin and carboplatin.

[0163] The term “platinum-resistant ovarian cancer” refers to ovarian cancer of subjects: a. who have only 1 line of systemic therapy and have completed a minimum of four cycles of platinum-based therapy with Complete Response (CR) or Partial Response (PR) and then progressed between 3 to 6 months after the last dose of platinum. b. who have received more than 1 line of platinum therapy and have progressed <6 months (<183 days) after the last dose of platinum.

[0164] The time is calculated from the date of last administrated dose of platinum-containing chemotherapy to the date of radiographic imaging with disease progression. A confirmed response of CR / PR means that a response of CR / PR is recorded at any time after the first platinum-containing chemotherapy treatment using radiographic imaging and confirmed by repeated radiographic imaging not less than 4 weeks after the response was first observed with no evidence of progression between the initial radiographic imaging and repeated radiographic imaging.

[0165] The term “progression-free survival” (PFS) as used herein refers to the time period between the first treatment of a subject suffering from cancer with an active agent, therapeutically effective agent, or pharmaceutical composition and the first objective tumor progression according to RECIST vl.l or death from any cause, whichever occurs first. PFS as used herein is determined over a period of 48 months.

[0166] The term “plurality” refers to the state of being plural.

[0167] The terms “polynucleotide” and “nucleic acid” can be used interchangeably herein to refer to polymers of nucleotides. The term “polynucleotide” comprises deoxyribonucleic acid (DNA), ribonucleic acid (RNA), combinations thereof, and modified forms thereof. The term comprises genomic DNA, cDNA, mRNA, recombinantly produced and chemically synthesized molecules. In some embodiments, a polynucleotide is DNA. In some

[0168] BNT ref. [P1955WO01] / / C&F ref. [241010WO] embodiments, a polynucleotide is RNA. A polynucleotide may be present as a mixture of DNA and RNA. A polynucleotide may be further present as a single-stranded or doublestranded and linear or covalently circularly closed molecule. A polynucleotide can be isolated. The term “isolated polynucleotide “ means that the polynucleotide (i) was amplified in vitro, for example via polymerase chain reaction (PCR) for DNA or in vitro transcription (using, e.g., an RNA polymerase) for RNA, (ii) was produced recombinantly by cloning, (iii) was purified, for example, by cleavage and separation by gel electrophoresis, or (iv) was synthesized, for example, by chemical synthesis.

[0169] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to polymers of amino acids.

[0170] The term “recombinant” when used in the context of a polynucleotide means a polynucleotide having nucleotide sequences that are not naturally joined together and can be made by artificially combining two otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, for example, by genetic engineering techniques. Recombinant polynucleotides include vectors comprising an amplified or assembled polynucleotide, which can be used to transform or transfect a suitable host cell. A host cell that comprises the recombinant polynucleotide is referred to as a “recombinant host cell.” The polynucleotide is then expressed in the recombinant host cell to produce a “recombinant polypeptide.” A recombinant polynucleotide can also comprise a non-coding function.

[0171] The term “RNA” relates to a nucleic acid molecule which includes ribonucleotide residues. In some embodiments, the RNA contains all or a majority of ribonucleotide residues. As used herein, “ribonucleotide” refers to a nucleotide with a hydroxyl group at the 2'-position of a P-D-ribofuranosyl group. RNA encompasses without limitation, double stranded RNA, single stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as modified RNA that differs from naturally occurring RNA by the addition, deletion, substitution and / or alteration of one or more nucleotides. Such alterations may refer to addition of non-nucleotide material to

[0172] BNT ref. [P1955WO01] / / C&F ref. [241010WO] internal RNA nucleotides or to the end(s) of RNA. It is also contemplated herein that nucleotides in RNA may be non-standard nucleotides, such as chemically synthesized nucleotides or deoxynucleotides. For the present invention, these altered / modified nucleotides can be referred to as analogs of naturally occurring nucleotides, and the corresponding RNAs containing such altered / modified nucleotides (i.e., altered / modified RNAs) can be referred to as analogs of naturally occurring RNAs. A molecule contains “a majority of ribonucleotide residues” if the content of ribonucleotide residues in the molecule is more than 50% (such as at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%), based on the total number of nucleotide residues in the molecule. The total number of nucleotide residues in a molecule is the sum of all nucleotide residues (irrespective of whether the nucleotide residues are standard (i.e., naturally occurring) nucleotide residues or analogs thereof). The term “RNA” further includes mRNA, tRNA, ribosomal RNA (rRNA), small nuclear RNA (snRNA), self-amplifying RNA (saRNA), trans-amplifying RNA (taRNA), single-stranded RNA (ssRNA), dsRNA, inhibitory RNA (such as antisense ssRNA, small interfering RNA (siRNA), or microRNA (miRNA)), activating RNA (such as small activating RNA) and immunostimulatory RNA (isRNA). In some embodiments, “RNA” refers to mRNA. RNA as described herein may comprise in vitro transcribed RNA (IVT-RNA) and may be obtained by in vitro transcription of an appropriate DNA template. The promoter for controlling transcription can be any promoter for any RNA polymerase. A DNA template for in vitro transcription may be obtained by cloning of a nucleic acid, in particular cDNA, and introducing it into an appropriate vector for in vitro transcription. The cDNA may be obtained by reverse transcription of RNA.

[0173] The term “separate administration” as used herein refers to the administration of at least two active agents or therapeutically effective agents using different pharmaceutical compositions or formulations. For example, the anti-CTLA4 antibody and the anti-PD-1 antibody of the present disclosure can be administered using two different pharmaceutical compositions, each comprising either the anti-CTLA4 antibody disclosed herein or the anti- PD-1 antibody disclosed herein.

[0174] BNT ref. [P1955WO01] / / C&F ref. [241010WO] “Systemic therapy” or “systemic treatment” is a therapy or treatment that targets the entire body, such as chemotherapy.

[0175] The term “treatment cycle” as used herein refers to the repetitive treatment of a subject with an active agent, therapeutically effective agent, or pharmaceutical composition, or combinations thereof. A treatment cycle begins with the administration of a first dosage of an active agent, therapeutically effective agent, or pharmaceutical composition, or combinations thereof and ends either with the administrations of a consecutive or subsequent dosage of the same or another active agent, therapeutically effective agent, or pharmaceutical composition, or combinations thereof or with the end of the treatment. In some embodiments a treatment cycle has at least about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days. In some preferred embodiments a treatment cycle has up to about 18 to about 28 days.

[0176] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it was individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0177] All patents, patent applications, and other publications cited in this application are incorporated by reference in the entirety for all purposes.

[0178] The anti-CTLA4 antibody and the anti-PD-1 antibody combination therapy of the invention

[0179] The present invention provides an anti-CTLA4 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject:

[0180] BNT ref. [P1955WO01] / / C&F ref. [241010WO] a) the anti-CTLA4 antibody; and b) an anti -PD-1 antibody, wherein the anti-CTLA4 antibody comprises:

[0181] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0182] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0183] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0184] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set

[0185] BNT ref. [P1955WO01] / / C&F ref. [241010WO] forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0186] The present invention provides antibodies thereof that immunospecifically bind to CTLA4, in particular human CTLA4, preferably expressed on the surface of a cell at an endogenous or transfected concentration. Cytotoxic T lymphocyte antigen-4 (CTLA4) is a regulator of adaptive immune responses, having a role in the maintenance of peripheral tolerance and in shaping the repertoire of emergent T cell responses. CTLA4 is expressed on the surface of cells and, if it is located at the surface of said cells, is accessible to binding by CTLA4- specific antibodies.

[0187] In some embodiments, the anti-CTLA4 antibody is capable of binding to human CTLA4. In some embodiments, CTLA4 is expressed on the surface of a T cell. In some embodiments, the anti-CTLA4 antibody is a monoclonal antibody, a human antibody, a chimeric antibody, or a humanized antibody. In some embodiments, the anti-CTLA4 antibody is a humanized anti-CTLA4 antibody. In some preferred embodiments, the anti-CTLA4 antibody is a humanized anti-CTLA4 IgGl monoclonal antibody.

[0188] Without wishing to be bound by theory, CTLA4 is contemplated to be recycled between the cell surface and endosomes, where it is usually prevented from lysosomal degradation and can recycle back to the cell surface by binding to the lipopolysaccharide-responsive and beige-like anchor (LRBA) protein. The anti-CTLA4 antibodies disclosed herein have reduced autoimmune side effects when used to enhance immune responses and are particularly suitable for treating platinum -resistant ovarian cancer in subjects.

[0189] In some embodiments, the subject in need for cancer treatment is a human.

[0190] In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0191] BNT ref. [P1955WO01] / / C&F ref. [241010WO] The anti-CTLA4 antibody described herein is combined with the anti-PD-1 antibody for treating subjects afflicted with platinum-resistant ovarian cancer. Without wishing to be bound by theory, it is contemplated herein that the anti-PD-1 antibody in combination with anti-CTLA4 antibodies is particularly effective for the treatment of platinum-resistant ovarian cancer patients.

[0192] Surprisingly, the combination method of the present invention comprising administration of the anti-CTLA4 antibody and the anti-PD-1 antibody shows an enhanced anti-cancer efficacy compared to administration of the anti-PD-1 antibody alone. Furthermore, the combination of the anti-CTLA4 antibody and the anti-PD-1 antibody shows good safety profiles in platinum-resistant ovarian cancer subjects. Furthermore, immune-related adverse events are reduced by the combination therapy of the invention. Immune-related adverse events such as skin rash, hepatitis, colitis and endocrinopathies, particularly hypopituitarism are characteristic side effects of anti-cancer therapies based on immune checkpoint inhibitors such as anti-CTLA4 antibodies. It was therefore surprising that the combination therapy of the invention improves the efficiency of the anti-cancer treatment while in parallel reducing undesired side effects, e.g., immune-related adverse events.

[0193] The anti-CTLA4 antibody

[0194] In some embodiments, the anti-CTLA4 antibody is capable of binding human CTLA4. The term “binding” preferably relates to a specific binding. An antibody usually is capable of binding to a predetermined target if it has a significant affinity for said predetermined target and binds to said predetermined target in standard assays. “Affinity” or “binding affinity” is often measured by equilibrium dissociation constant (KD). Preferably, the term “significant affinity” refers to the binding to a predetermined target with a dissociation constant (KD) of 10'5M or lower, 10'6M or lower, 10'7M or lower, 10'8M or lower, or 10'9M or lower. An antibody is not (substantially) capable of binding to a target if it has no significant affinity for said target and does not bind significantly, in particular does not bind detectably, to said target in standard assays. For example, if the KD for binding of an antibody to the target to which the antibody is capable of binding is 10'9M, the KD for binding to a target for which

[0195] BNT ref. [P1955WO01] / / C&F ref. [241010WO] the antibody has no significant affinity would be is at least around 10'8M, 10'7M, 10'6M, IO’5M, IO’4M, IO’3M, IO’2M, or IO’1M.

[0196] Binding of an antibody to a target can be determined experimentally using any suitable method; see, for example, Berzofsky et al., Antibody- Antigen Interactions In Fundamental Immunology, Paul, W. E., Ed., Raven Press New York, N Y (1984), Kuby, Janis Immunology, W. H. Freeman and Company New York, N Y (1992), and methods described herein. Affinities may be readily determined using conventional techniques, such as by equilibrium dialysis; by using the BIAcore 2000 instrument, using general procedures outlined by the manufacturer; by radioimmunoassay using radiolabeled target antigen; or by another method known to the skilled artisan. The affinity data may be analyzed, for example, by the method of Scatchard et al. (Scatchard et al., Ann NY Acad ScL 1949, 51 :660). The measured affinity of a particular antibody-antigen interaction can vary if measured under different conditions, e.g., salt concentration, pH. Thus, measurements of affinity and other antigen-binding parameters, e.g., KD, IC50, are preferably made with standardized solutions of antibody and antigen, and a standardized buffer. For example, the affinity of an antibody can be evaluated by Octet. Multi -concentration kinetic experiments can be performed on the Octet Red96 system (ForteBio). Anti-hlgG Fc biosensors (ForteBio, #18-5064) can be hydrated in sample diluent (0.1% BSA in PBS and 0.02% Tween 20) and preconditioned in pH 1.7 glycine. The antigen can be diluted using a 7- point, 2-fold serial dilution starting at 600 nM with sample diluent. The antibody to be tested can be diluted to 10 pg / mL with sample diluent and then immobilized onto anti-hlgG Fc biosensors for 120 seconds. After baselines are established for 60 seconds in sample diluent, the biosensors can be moved to wells containing the antigen at a series of concentrations to measure the association. Association can be observed (e.g., for 120 seconds) and dissociation can be observed (e.g., for 180 seconds) for each protein of interest in the sample diluent. The binding affinities can be characterized by fitting the kinetic sensorgrams to a monovalent binding model (1 : 1 binding).

[0197] The anti-CTLA4 antibody disclosed herein is specific for CTLA4 if it is capable of binding to CTLA4 but is not (substantially) capable of binding to other targets.

[0198] BNT ref. [P1955WO01] / / C&F ref. [241010WO] The anti-CTLA4 antibody disclosed herein preferably does not inhibit binding of human CTLA4 to the B7.1 (CD80) and B7.2 (CD86) ligands of antigen presenting cells. In some embodiments, the level of B7.1 and B7.2 on immune cells following anti-CTLA4 treatment is used as a biomarker for measuring the biological activity of anti-CTLA4 antibodies in vivo and monitoring responses to anti-CTLA4 treatment by measuring the level B7.1 and / or B7.2 expression on immune cells, and comparing the level of expression before and after treatment. In some embodiments, the level of B7.1 and / or B7.2 expression is monitored over time during a course of therapy. The therapeutic effect of anti-CTLA4 antibodies disclosed herein is preferably achieved through antibody-mediated depletion of Tregs specifically within tumor microenvironment. The anti-CTLA4 antibodies disclosed herein are preferably not capable of blocking B7-CTLA4 interactions under physiological conditions.

[0199] A fundamental question for the generation of safe and effective anti-CTLA4 antibodies is whether cancer immunotherapeutic effects (CITE) and immunotherapy -related adverse effects (irAE) are intrinsically linked. The classical checkpoint blockade hypothesis stipulated that anti-CTLA4 antibodies promote cancer immunity by blocking a negative signal of B7-CTLA4 interactions to promote naive T cell activation in the lymphoid organ. According to this model, therapeutic antibodies are antagonists that functionally inactivate CTLA4-B7 interactions. Since genetic inactivation of CTLA4 expression leads to autoimmune diseases in mouse and human, it was assumed that the irAE would be a necessary price for CITE. However, there is no evidence to date that blocking CTLA4 interaction with B7.1 and B7.2 is either necessary or sufficient for the CITE of anti-CTLA4 antibodies. Without wishing to be bound by theory, it is contemplated that selective depletion of Tregs in the tumor microenvironment constitutes the main mechanism of action of anti-CTLA4 antibodies. It is not relevant whether an antibody is capable of blocking B7-CTLA4 interactions under physiological conditions for the induction of CITE. In some embodiments, the anti-CTLA4 antibody disclosed herein can induce CITE without blocking B7-CTLA4 interactions.

[0200] BNT ref. [P1955WO01] / / C&F ref. [241010WO] In particularly preferred embodiments, the anti-CTLA4 antibody is described in International Patent Application Publication No. WO 2017 / 106372, which is incorporated herein in its entirety.

[0201] In some embodiments, the anti-CTLA4 antibody comprises: a) a heavy chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 7, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 7; and b) a light chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 8, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 8.

[0202] In some embodiments, the antibody having the ability to bind to CTLA4 can be a monoclonal antibody. In some embodiments, the anti-CTLA4 antibody is an IgGl antibody. The term “monoclonal antibody” as used herein refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody displays a single binding specificity and affinity. In some embodiments, the monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a non-human animal, e.g., mouse, fused to an immortalized cell.

[0203] In some embodiments, the anti-CTLA4 antibody comprises a constant region. In some preferred embodiments, the constant region of the anti-CTLA4 antibody is derived from a human antibody. In some preferred embodiments, the constant region is derived from a human antibody. In some preferred embodiments, the constant region of the anti-CTLA4 antibody is a constant region of human IgGl.

[0204] In some embodiments, the anti-CTLA4 antibody comprises an IgGl Fc region (or IgGl Fc domain). In some embodiments, the anti-CTLA4 antibody comprises an IgGl Fc region comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 9 or an amino acid sequence comprising at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity

[0205] BNT ref. [P1955WO01] / / C&F ref. [241010WO] to SEQ ID NO: 9. In such embodiments, the anti-CTLA4 antibody comprises a mutated Fc region. Relative to the sequence of the IgGl backbone in SEQ ID NO: 14, the mutations are M135Y, S137T, T139E, S181A, E216A, and K217A. These mutations are contemplated to lead to increased antibody dependent cellular cytotoxicity (ADCC) and increased half-life of the antibody in vivo.

[0206] In some embodiments, the anti-CTLA4 antibody comprises: a) a heavy chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 10 or an amino acid sequence comprising at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10; and b) a light chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 12 or an amino acid sequence comprising at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 12.

[0207] In some embodiments, the anti-CTLA4 antibody comprises: a) a heavy chain whose amino acid sequence is encoded by a nucleotide sequence set forth in SEQ ID NO: 11 or a nucleotide sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 11; and b) a light chain whose amino acid sequence is encoded by a nucleotide sequence set forth in SEQ ID NO: 13 or a nucleotide sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 13.

[0208] In some embodiments, the thymidine in the nucleotide sequences set forth in SEQ ID NO: 11 or 13 is uridine. Meaning, all thymidines present in the nucleotide sequences of SEQ ID NO: 11 or 13 can be uridines.

[0209] In some embodiments, the anti-CTLA4 antibody is a pH-sensitive anti-CTLA4 antibody or a pH-sensitive anti-CTLA4 antibody fragment. For example, the pH-sensitive anti-CTLA4

[0210] BNT ref. [P1955WO01] / / C&F ref. [241010WO] antibody or anti-CTLA4 antibody fragment can dissociate from CTLA4 at pH 6.5 or below, more preferably pH 5.5 or below. In some preferred embodiments, binding to CTLA4 is reduced at an endosomal pH of 5.5 by more than 50% relative to binding at neutral pH (pH 7.0). Such a reduction may reach more than 75% at lysosomal pH 4.5 as compared to pH 7.0. The antibody- antigen complex preformed at pH 7.0 may dissociate under an acidic environment of pH 4.5-6.0. The reduction in binding may also be in comparison to a reference antibody which may be considerably less pH-sensitive using the same standard. The reference antibody may be an antibody known in the art such as Ipilimumab or Tremelimumab. In the context of an engineered antibody or antibody fragment, the changes may also be in comparison to a wild-type antibody or antibody fragment which may be considerably less pH-sensitive using the same standard. Without wishing to be bound by theory, it is contemplated that a pH-sensitive antibody or antibody fragment is not only safer but also more effective in Treg depletion and tumor rejection than a pH-insensitive anti-CTLA4 antibody (e.g., Ipilimumab) or a fragment thereof. Meaning, Ipilimumab can bind to CTLA4 at a pH of 4-7 and no dissociation can be observed at pH 4-7. pH- insensitive antibodies can cause down-regulation of CTLA4 through lysosomal degradation. CTLA4 down-regulation can cause autoimmune diseases, while in the tumor CTLA4 down-regulation can reduce ADCC activity and thus anti-cancer efficacy. The sensitivity to pH can be measured by any method known to the skilled person. For example, human or monkey-CTLA4-Fc or (0.5 pg / ml) can be coated on ELISA plates at 4°C overnight. Biotinylated anti-CTLA4 antibodies anti-CTLA4 antibody fragments can be added at 1 pg / ml in 1% BSA PBS with pH 4.5-7.0. Two hours later, antibodies and antibody fragments binding with or to CTLA4 can be measured by using HRP -labeled streptavidin.

[0211] Although the following provides considerations regarding the mechanism underlying the therapeutic efficacy of antibodies of the disclosure it is not to be considered as limiting to the invention in any way. In some embodiments, the antibodies are contemplated to be a highly selective, humanized monoclonal immunoglobulin G1 (IgGl)-kappa isotype antibody against CTLA4 with a robust anti-tumor activity and lower autoimmune toxicity in comparison to ipilimumab. The disclosed antibodies preferably can dissociate from CTLA4 under low pH in endosomes to allow both CTLA4 and the antibody to escape from

[0212] BNT ref. [P1955WO01] / / C&F ref. [241010WO] lysosomal degradation and recycle to the cell surface. Unlike ipilimumab that down- regulates CTLA4 expression on Treg cells, the antibodies can keep a high-level expression of CTLA4 on Treg cells through this recycling mechanism and makes Treg cells a better target for antibody-dependent cellular cytotoxicity, particularly in the tumor microenvironment (TME). The selective elimination of Treg cells in the tumor microenvironment and maintenance of CTLA4 expression in Treg cells in the peripheral tissues by the anti-CTLA4 antibody is contemplated to form the cellular and molecular basis for more potent tumor rejection and low toxicity. For example, the anti-CTLA4 antibody described herein dissociates from CTLA4 in endosomes, allows normal recycling of both antibodies and CTLA4, which lead to a much-reduced autoimmune toxicity. The preservation of the recycling of both CTLA4 and the anti-CTLA4 antibody facilitates more potent ADCC to eliminate Treg cells in the tumor microenvironment and induces strong CITE. ADCC preferably occurs when antibodies bind to antigens such as CTLA4 on Treg cells and the antibody Fc regions engage Fc receptors (FcR) on the surface of immune effector cells.

[0213] Antibodies described herein and useful in the methods described herein can be produced by a variety of techniques, including conventional monoclonal antibody methodology, e.g., the standard somatic cell hybridization technique of Kohler and Milstein, Nature 1975, 256: 495. Although somatic cell hybridization procedures are preferred, in principle, other techniques for producing monoclonal antibodies can be employed, e.g., viral or oncogenic transformation of B -lymphocytes or phage display techniques using libraries of antibody genes.

[0214] In some embodiments, an animal system for preparing hybridomas that secrete monoclonal antibodies may be a murine system. Hybridoma production in the mouse is a very well- established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known.

[0215] BNT ref. [P1955WO01] / / C&F ref. [241010WO] Other preferred animal systems for preparing hybridomas that secrete monoclonal antibodies are the rat and the rabbit system (e.g., described in Spieker-Polet et al., Proc Natl Acad Sci U.S.A. 1995, 92: 9348; see also Rossi et al., Am J Clin Pathol 2005, 124: 295).

[0216] Yet another strategy for generating monoclonal antibodies is to directly isolate genes encoding antibodies from lymphocytes producing antibodies of defined specificity. For details of recombinant antibody engineering see also Welschof and Kraus, Recombinant antibodies for cancer therapy ISBN-0-89603-918-8 and Bemiy K.C. Lo Antibody Engineering ISBN 1 -58829- 092-1.

[0217] To generate antibodies, mice can be immunized with carrier-conjugated peptides derived from the antigen sequence, i.e., the sequence against which the antibodies are to be directed, an enriched preparation of recombinantly expressed antigen or fragments thereof and / or cells expressing the antigen, as described. Alternatively, mice can be immunized with nucleic acid encoding the antigen or fragments thereof. In the event that immunizations using a purified or enriched preparation of the antigen do not result in antibodies, mice can also be immunized with cells expressing the antigen, e.g., a cell line, to promote immune responses.

[0218] The immune response can be monitored over the course of the immunization protocol with plasma and serum samples being obtained by tail vein or retroorbital bleeds. Mice with sufficient titers of immunoglobulin can be used for fusions. Mice can be boosted intraperitoneally or intravenously with antigen expressing cells 3 days before sacrifice and removal of the spleen to increase the rate of specific antibody secreting hybridomas.

[0219] To generate hybridomas producing monoclonal antibodies, splenocytes and lymph node cells from immunized mice can be isolated and fused to an appropriate immortalized cell line, such as a mouse myeloma cell line. The resulting hybridomas can then be screened for the production of antigen-specific antibodies. Individual wells can then be screened by ELISA for antibody secreting hybridomas. By Immunofluorescence and FACS analysis using antigen expressing cells, antibodies with specificity for the antigen can be identified. The antibody secreting hybridomas can be re-plated, screened again, and if still positive for

[0220] BNT ref. [P1955WO01] / / C&F ref. [241010WO] monoclonal antibodies can be subcloned by limiting dilution. The stable subclones can then be cultured in vitro to generate antibody in tissue culture medium for characterization. Antibodies also can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as are well known in the art (Morrison, Science 1985, 229: 1202).

[0221] For example, in some embodiments, the gene(s) of interest, e.g., antibody genes, can be ligated into an expression vector such as a eukaryotic expression plasmid such as used by the GS gene expression system disclosed in International Patent Application Publication Nos. WO 87 / 04462 and WO 89 / 01036 and EP 338 841 A or other expression systems well known in the art. The purified plasmid with the cloned antibody genes can be introduced in eukaryotic host cells such as CHO cells, NS / 0 cells, HEK293T cells or HEK293 cells or alternatively other eukaryotic cells like plant derived cells, fungal or yeast cells. The method used to introduce these genes can be methods described in the art such as electroporation, lipofectine, lipofectamine or others. After introduction of these antibody genes in the host cells, cells expressing the antibody can be identified and selected. These cells represent the transfectomas which can then be amplified for their expression level and upscaled to produce antibodies. Recombinant antibodies can be isolated and purified from these culture supernatants and / or cells.

[0222] Alternatively, the cloned antibody genes can be expressed in other expression systems, including prokaryotic cells, such as microorganisms, e.g., E. coli. Furthermore, the antibodies can be produced in transgenic non-human animals, such as in milk from sheep and rabbits or in eggs from hens, or in transgenic plants; see e.g., Verma, R., et al., J Immunol Meth 1998,216: 165-181; Pollock, et al., J Immunol Meth 1999, 231 : 147-157; and Fischer, R., et al., Biol Chem 1999, 380: 825-839.

[0223] Antibodies interact with target antigens predominantly through amino acid residues that are located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within CDRs are more diverse between individual antibodies than sequences outside of CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that

[0224] BNT ref. [P1955WO01] / / C&F ref. [241010WO] mimic the properties of specific naturally occurring antibodies by constructing expression vectors that include CDR sequences from the specific naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann et al., Nature 1998, 332:323-327; Jones et al., Nature 1986, 321 :522-525; and Queen et al., Proc Natl Acad Sci USA 1989, 86: 10029-10033). Such framework sequences can be obtained from public DNA databases that include germline antibody gene sequences. These germline sequences will differ from mature antibody gene sequences because they will not include completely assembled variable genes, which are formed by V (D) J joining during B cell maturation. Germline gene sequences will also differ from the sequences of a high affinity secondary repertoire antibody at individual evenly across the variable region.

[0225] The ability of antibodies to bind an antigen can be determined using standard binding assays (e.g., ELISA, Western Blot, Immunofluorescence and flow cytometric analysis).

[0226] To purify antibodies, selected hybridomas can be grown in two-liter spinner- flasks for monoclonal antibody purification. Alternatively, antibodies can be produced in dialysisbased bioreactors. Supernatants can be filtered and, if necessary, concentrated before affinity chromatography with protein G-sepharose or protein A-sepharose. Eluted IgG can be checked by gel electrophoresis and high-performance liquid chromatography to ensure purity. The buffer solution can be exchanged into PBS, and the concentration can be determined by OD280 using 1.43 extinction coefficient. The monoclonal antibodies can be ali quoted and stored at -80°C.

[0227] To determine if selected monoclonal antibodies bind to unique epitopes and / or to characterize one or more binding properties, site-directed or multi-site directed mutagenesis can be used.

[0228] To determine the isotype of antibodies, isotype ELISAs with various commercial kits (e.g., Zymed, Roche Diagnostics) can be performed. Wells of microtiter plates can be coated with anti-mouse Ig. After blocking, the plates are reacted with monoclonal antibodies or purified isotype controls, at ambient temperature for two hours. The wells can then be reacted with

[0229] BNT ref. [P1955WO01] / / C&F ref. [241010WO] either mouse IgGl, IgG2a, IgG2b or IgG3, IgA or mouse IgM-specific peroxidase- conjugated probes. After washing, the plates can be developed with ABTS substrate (1 mg / ml) and analyzed at OD of 405-650. Alternatively, the IsoStrip Mouse Monoclonal Antibody Isotyping Kit (Roche, Cat. No. 1493027) may be used as described by the manufacturer.

[0230] In order to demonstrate presence of antibodies in sera of immunized mice or binding of monoclonal antibodies to living cells expressing antigen, flow cytometry can be used. Cell lines expressing naturally or after transfection antigen and negative controls lacking antigen expression (grown under standard growth conditions) can be mixed with various concentrations of monoclonal antibodies in hybridoma supernatants or in PBS containing 1 % FBS, and can be incubated at 4 °C for 30 min. After washing, the APC- or Alexa647- labeled anti IgG antibody can bind to antigen-bound monoclonal antibody under the same conditions as the primary antibody staining. The samples can be analyzed by flow cytometry with a FACS instrument using light and side scatter properties to gate on single, living cells. In order to distinguish antigen-specific monoclonal antibodies from nonspecific binders in a single measurement, the method of co-transfection can be employed. Cells transiently transfected with plasmids encoding antigen and a fluorescent marker can be stained as described above. Transfected cells can be detected in a different fluorescence channel than antibody-stained cells. As the majority of transfected cells express both transgenes, antigen- specific monoclonal antibodies bind preferentially to fluorescence marker expressing cells, whereas non-specific antibodies bind in a comparable ratio to nontransfected cells. An alternative assay using fluorescence microscopy may be used in addition to or instead of the flow cytometry assay. Cells can be stained exactly as described above and examined by fluorescence microscopy.

[0231] In order to demonstrate presence of antibodies in sera of immunized mice or binding of monoclonal antibodies to living cells expressing antigen, immunofluorescence microscopy analysis can be used. For example, cell lines expressing either spontaneously or after transfection antigen and negative controls lacking antigen expression are grown in chamber slides under standard growth conditions in DMEM / F12 medium, supplemented with 10 % fetal calf serum (FCS), 2 raM L-glutamine, 100 lU / ml penicillin and 100 pg / ml

[0232] BNT ref. [P1955WO01] / / C&F ref. [241010WO] streptomycin. Cells can then be fixed with methanol or paraformaldehyde or left untreated. Cells can then be reacted with monoclonal antibodies against the antigen for 30 min. at 25°C. After washing, cells can be reacted with an Alexa555-labelled anti-mouse IgG secondary antibody (Molecular Probes) under the same conditions. Cells can then be examined by fluorescence microscopy.

[0233] Cell extracts from cells expressing antigen and appropriate negative controls can be prepared and subjected to sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. After electrophoresis, the separated antigens will be transferred to nitrocellulose membranes, blocked, and probed with the monoclonal antibodies to be tested. IgG binding can be detected using anti-mouse IgG peroxidase and developed with ECL substrate.

[0234] Antibodies can be further tested for reactivity with antigen by Immunohistochemistry in a manner well known to the skilled person, e.g., using paraformaldehyde or acetone fixed cryosections or paraffin embedded tissue sections fixed with paraformaldehyde from noncancer tissue or cancer tissue samples obtained from patients during routine surgical procedures or from mice carrying xenografted tumors inoculated with cell lines expressing spontaneously or after transfection antigen. For immunostaining, antibodies reactive to antigen can be incubated followed by horseradish-peroxidase conjugated goat anti-mouse or goat anti-rabbit antibodies (DAKO) according to the vendors instructions. The testing of monoclonal antibody activity in vitro will provide an initial screening prior to testing in vivo models.

[0235] In some embodiments, the anti-CTLA4 antibody is encoded by one or more nucleic acid molecules.

[0236] The anti-PD-1 antibody

[0237] The anti-PD-1 antibody is capable of binding human PD-1. Examples of mAbs that bind to human PD-1, useful in the treatment methods, compositions, and uses of the invention, are described in US 7,521,051, US 8,008,449, and US 8,354,509. Specific anti-human PD-1

[0238] BNT ref. [P1955WO01] / / C&F ref. [241010WO] mAbs useful as the PD-1 antagonist in the treatment methods, compositions, kits, and uses of the present invention include: pembrolizumab (formerly known as MK-3475, SCH 900475 and lambrolizumab), a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences shown in FIGURE 1, and the humanized antibodies h409Al l, h409A16 and h409A17, which are described in WO 2008 / 156712.

[0239] Provided herein are PD-1 antagonists or anti-human PD-1 monoclonal antibodies that can be used in any of the methods, compositions, kits, and uses disclosed herein, including any chemical compound or biological molecule that blocks binding of PD-L1 to PD-1 and preferably also blocks binding of PD-L2 to PD-1.

[0240] Any monoclonal antibodies that bind to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and block the interaction between PD-1 and its ligand PD-L1 or PD-L2 can be used. In some embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1. In other embodiments, the anti -human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L2. In yet other embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1 and the interaction between PD-1 and PD-L2.

[0241] Any monoclonal antibodies that bind to a PD-L1 polypeptide, a PD-L1 polypeptide fragment, a PD-L1 peptide, or a PD-L1 epitope and block the interaction between PD-L1 and PD-1 can also be used.

[0242] In some embodiments, the anti-human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, pidilizumab (U.S. Pat. No. 7,332,582), AMP-514 (Medlmmune LLC, Gaithersburg, MD), PDR001 (U.S. Pat. No. 9,683,048), BGB-A317 (U.S. Pat. No. 8,735,553), and MGA012

[0243] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (MacroGenics, Rockville, MD). In some preferred embodiments, the anti-human PD-1 monoclonal antibody is pembrolizumab. In some embodiments, the anti-human PD-1 monoclonal antibody is nivolumab. In some embodiments, the anti-human PD-1 monoclonal antibody is cemiplimab. In some embodiments, the anti-human PD-1 monoclonal antibody is dostarlimab. In some embodiments, the anti-human PD-1 monoclonal antibody is pidilizumab. In some embodiments, the anti-human PD-1 monoclonal antibody is AMP-514. In some embodiments, the anti-human PD-1 monoclonal antibody is PDR001.

[0244] In some embodiments, the anti-human PD-1 monoclonal antibody is BGB-A317. In some embodiments, the anti-human PD-1 monoclonal antibody is MGA012.

[0245] In some embodiments, the anti -human PD-1 antibody or antigen binding fragment thereof for use in the treatment methods, compositions, kits, and uses of the invention comprises three light chain CDRs of LCDR1, LCDR2 and LCDR3 and / or three heavy chain CDRs of HCDR1, HCDR2 and HCDR3.

[0246] In some embodiments, LCDR1 comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 18 or a variant of the amino acid sequence as set forth in SEQ ID NO: 18, LCDR2 comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 19 or a variant of the amino acid sequence as set forth in SEQ ID NO: 19, and LCDR3 comprises or consists of the amino acid sequence as set forth in SEQ ID NO:20 or a variant of the amino acid sequence as set forth in SEQ ID NO:20.

[0247] In some embodiments, HCDR1 comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 15 or a variant of the amino acid sequence as set forth in SEQ ID NO:15, HCDR2 comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 16 or a variant of the amino acid sequence as set forth in SEQ ID NO: 16, and HCDR3 comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 17 or a variant of the amino acid sequence as set forth in SEQ ID NO: 17.

[0248] In some embodiments, the three light chain CDRs (LCDR1-3) comprise or consist of the amino acid sequences as set forth in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO:20

[0249] BNT ref. [P1955WO01] / / C&F ref. [241010WO] and the three heavy chain CDRs (HCDR1-3) comprise or consist of the amino acid sequences as set forth in SEQ ID NO: 15, SEQ ID NO: 16 and SEQ ID NO: 17.

[0250] In some embodiments, the anti-PD-1 antibody disclosed herein comprises:

[0251] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0252] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0253] Some anti-human PD-1 antibody and antigen binding fragments of the invention comprise a light chain variable region and a heavy chain variable region. In some embodiments, the light chain variable region comprises or consists of the amino acid sequence as set forth in SEQ ID NO:22 or a variant of the amino acid sequence as set forth in SEQ ID NO:22, and the heavy chain variable region comprises or consists of the amino acid sequence as set forth in SEQ ID NO:21 or a variant of the amino acid sequence as set forth in SEQ ID NO:21.

[0254] In such embodiments, a light chain variable region or heavy chain variable region sequence is identical to the reference sequence except having one, two, three, four or five amino acid substitutions. In some embodiments, the substitutions are in the framework region (z.e.,

[0255] BNT ref. [P1955WO01] / / C&F ref. [241010WO] outside of the CDRs). In some embodiments, one, two, three, four or five of the amino acid substitutions are conservative substitutions.

[0256] In some embodiments, the anti -human PD-1 antibody or antigen binding fragment comprises a light chain variable domain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:22 and a heavy chain variable domain comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:21.

[0257] In some embodiments, the anti-human PD-1 antibody or antigen binding protein comprises or consists of a VL domain and / or a VH domain with at least 95%, 90%, 85%, 80%, 75% or 50% sequence homology to one of the VL domains or VH domains described above, and exhibits specific binding to PD-1. In some embodiments, the anti-human PD-1 antibody or antigen binding protein comprises or consist of VL and VH domains having up to 1, 2, 3, 4, or 5 or more amino acid substitutions, and exhibits specific binding to PD-1.

[0258] In some embodiments, the anti-PD-1 antibody comprises: a) a heavy chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 21, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 21; and b) a light chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 22, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 22.

[0259] In some embodiments, the PD-1 antagonist may be a full-length anti-PD-1 antibody or an antigen binding fragment thereof that specifically binds human PD-1. In some embodiments, the PD-1 antagonist is a full-length anti-PD-1 antibody selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE. Preferably, the anit-PD- 1 antibody is an IgG antibody. Any isotype of IgG can be used, including IgGi, IgG?, IgGs,

[0260] BNT ref. [P1955WO01] / / C&F ref. [241010WO] and IgG4. Different constant domains may be appended to the VL and VH regions provided herein. For example, if a particular intended use of an antibody (or fragment) of the present invention were to call for altered effector functions, a heavy chain constant domain other than IgGl may be used. Although IgGl antibodies provide for long half-life and for effector functions, such as complement activation and antibody-dependent cellular cytotoxicity, such activities may not be desirable for all uses of the antibody. In such instances an IgG4 constant domain, for example, may be used.

[0261] In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:24 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 23.

[0262] In some embodiments, the anti-PD-1 antibody comprises: a) a heavy chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 23 or an amino acid sequence comprising at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 23; and b) a light chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 24 or an amino acid sequence comprising at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 24.

[0263] In some preferred embodiments of the invention, the PD-1 antagonist is pembrolizumab or a pembrolizumab biosimilar.

[0264] Table 1. Exemplary PD-1 Antibody Sequences

[0265] BNT ref. [P1955WO01] / / C&F ref. [241010WO]

[0266] In some embodiments of the invention, the PD-1 antagonist or the anti-PD-1 antibody in the combination therapy comprising the anti-CTLA4 antibody and the anti-PD-1 antibody is pembrolizumab, or a pembrolizumab variant, that is administered in a liquid medicament at a dose selected from the group consisting of 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / kg Q2W, 5 mg / kg Q2W, 10 mg / kg Q2W, 1 mg / kg Q3W, 2 mg / kg Q3W, 3 mg / kg Q3W, 5 mg / kg Q3W, 10 mg / kg Q3W and flat-dose equivalents of any of these doses, i.e., such as 200 mg Q3W or 400 mg Q6W. In some embodiments, pembrolizumab is provided as a liquid medicament that comprises 25 mg / ml pembrolizumab, 7% (w / v) sucrose, 0.02% (w / v) polysorbate 80 in 10 mM histidine buffer pH 5.5. In some embodiments, pembrolizumab is provided as a liquid medicament that comprises about 125 to about 200

[0267] BNT ref. [P1955WO01] / / C&F ref. [241010WO] mg / mL of pembrolizumab, or an antigen binding fragment thereof; about 10 mM histidine buffer; about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof; about 7% (w / v) sucrose; and about 0.02 % (w / v) polysorbate 80.

[0268] In some embodiments, the selected dose of pembrolizumab is administered by IV infusion. In some embodiments, the selected dose of pembrolizumab is administered by IV infusion over a time period of between 25 and 40 minutes, or about 30 minutes. In some embodiments, the selected dose of pembrolizumab is administered by subcutaneous injection.

[0269] In some embodiments, the PD-1 antagonist or the anti-PD-1 antibody in the combination therapy comprising the anti-CTLA4 antibody and the anti-PD-1 antibody is pembrolizumab, or a pembrolizumab variant, that is adminsitered in a liquid medicament at a dose selected from about 280 mg to about 450 mg administered every approximately three weeks. In some embodiments, the selected dose of pembrolizuamb is administered subcutaneously.

[0270] “Anti-PD-1 antibody” as used in any of the treatment methods, compositions, kits, and uses of the present invention include monoclonal antibodies (mAb), or antigen binding fragments thereof, which specifically bind to human PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the treatment methods, compositions, kits, and uses of the invention in which a human individual is being treated, the anti-PD-1 antibody, or antigen binding fragment thereof, is a PD-1 antagonist that blocks binding of human PD-L1 to human PD-1, or blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No. : NP 054862 and NP 079515, respectively. An anti-PD-1 antibody may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments the human constant region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in particular embodiments, the human constant

[0271] BNT ref. [P1955WO01] / / C&F ref. [241010WO] region is an IgGl or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.

[0272] The "Programmed Death-1 (PD-1)" receptor refers to an immuno-inhibitory receptor belonging to the CD28 family. PD-1 (also known as CD279) is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). The term "PD-1 " as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1.

[0273] "Programmed Death Ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulates T cell activation and cytokine secretion upon binding to PD-1. The term "PD-L1" as used herein includes human PD-L1 (hPD-Ll), variants, isoforms, and species homologs of hPD-Ll, such as macaque (cynomolgus monkey), African elephant, wild boar and mouse PD-L1 (cf., e.g., Genbank accession no. NP 054862.1, XP 005581836, XP 003413533, XP 005665023 and NP 068693, respectively), and analogs having at least one common epitope with hPD-Ll.

[0274] The term "PD-L2" as used herein includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogs having at least one common epitope with hPD- L2. The ligands of PD-1 (PD-L1 and PD-L2) are expressed on the surface of antigen- presenting cells, such as dendritic cells or macrophages, and other immune cells. Binding of PD-1 to PD-L1 or PD-L2 results in downregulation of T cell activation. Cancer cells expressing PD-L1 and / or PD-L2 are able to switch off T cells expressing PD-1 what results in suppression of the anticancer immune response. The interaction between PD-1 and its ligands results in a decrease in tumor infiltrating lymphocytes, a decrease in T cell receptor mediated proliferation, and immune evasion by the cancerous cells. Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.

[0275] BNT ref. [P1955WO01] / / C&F ref. [241010WO] “Conservatively modified variants” or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g. charge, side-chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and / or specificity. Those of skill in the art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in the below Table.

[0276] Table 2: Exemplary Conservative Amino Acid Substitutions 1

[0277] BNT ref. [P1955WO01] / / C&F ref. [241010WO]

[0278] “Diagnostic anti-PD-L monoclonal antibody” means a mAb which specifically binds to the mature form of the designated PD-L (PD-L1 or PD-L2) that is expressed on the surface of certain mammalian cells. A mature PD-L lacks the presecretory leader sequence, also referred to as leader peptide. The terms “PD-L” and “mature PD-L” are used interchangeably herein, and shall be understood to mean the same molecule unless otherwise indicated or readily apparent from the context.

[0279] Specific examples of diagnostic anti-human PD-L1 mAbs useful as diagnostic mAbs for immunohistochemistry (IHC) detection of PD-L1 expression in formalin-fixed, paraffin- embedded (FFPE) tumor tissue sections are antibody 20C3 and antibody 22C3, which are described in WO 2014 / 100079.

[0280] The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct from that of CTLA4, because both molecules regulate an overlapping set of signaling proteins.

[0281] BNT ref. [P1955WO01] / / C&F ref. [241010WO] Treatment

[0282] In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody (such a pembrolizumab) are administered separately, i.e. using two different pharmaceutical compositions each individually comprising the anti-CTLA4 antibody or the anti-PD-1 antibody disclosed herein. In some preferred embodiments, a dose of the anti-CTLA4 antibody and a dose of the anti-PD-1 antibody are administered separately. For example, a dose of the anti-CTLA4 antibody and a dose of the anti-PD-1 antibody are administered separately using two different pharmaceutical compositions, each individually comprising the anti-CTLA4 disclosed herein, or the anti-PD-1 antibody disclosed herein.

[0283] In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are administered consecutively.

[0284] In some preferred embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are administered separately and consecutively.

[0285] In some embodiments, the anti-PD-1 antibody can be administered first, followed by a rest before the anti-CTLA4 antibody can administered. The anti-CTLA4 antibody can be administered after administration of the anti-PD-1 antibody. In some embodiments, the anti-CTLA4 antibody can be administered first, followed a rest before the anti-PD-1 antibody can be administered. In some embodiments, the anti-PD-1 antibody can be administered after administration of the anti-CTLA4 antibody. Preferably, the anti-PD-1 antibody is administered before the anti-CTLA4 antibody is administered.

[0286] In some embodiments, the anti-PD-1 antibody can be administered over 20-50 minutes or 30-40 minutes. For example, the anti-PD-1 antibody can be administered over at least 20 minutes or at least 30 minutes, and up to 40 minutes or up to 50 minutes.

[0287] In some embodiments, the anti-CTLA4 antibody can be administered over 10-60 minutes, 20-50 minutes, or 30-40 minutes. For example, the anti-CTLA4 antibody can be administered for at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40

[0288] BNT ref. [P1955WO01] / / C&F ref. [241010WO] minutes, at least 50 minutes, at least 60 minutes. In some embodiments, the anti-CTLA4 antibody can be administered over at least 30 minutes for dose level of about 1.0 mg / kg or about 2.0 mg / kg.

[0289] In some embodiments, a treatment cycle has at least about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days. In some embodiments, a treatment cycle has up to about 18 to 28 days. In some embodiments, a treatment cycle has about 28 days. In some preferred embodiments, a treatment cycle has about 21 days. In this context, it is understood that a treatment cycle can vary about several days, e.g., a treatment cycle can have 18 to 28 days or 18 to 24 days.

[0290] In some embodiments, a treatment cycle is repeated at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 times, optionally at least 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, or 35 times. However, the treatment can be continued until disease progression or the initiation of a new anti-tumor treatment. In some embodiments, the anti- CTLA4 antibody and / or the anti-PD-1 antibody are administered for 17 to 35 treatment cycles or up to 1 to 2 years. In some embodiments, the anti-CTLA4 antibody and / or the anti-PD-1 antibody are administered for up to 35 treatment cycles or up to 2 years.

[0291] In some embodiments, the anti-CTLA4 antibody is administered about every 3-4 weeks. In some embodiments, the anti-CTLA4 antibody is administered about every 4 weeks. In some embodiments, the anti-CTLA4 antibody is administered about every 3 weeks.

[0292] In some embodiments, the anti-PD-1 antibody is administered about every 3-4 weeks. In some embodiments, the anti-PD-1 antibody is administered about every 4 weeks. In some embodiments, the anti-PD-1 antibody is administered about every 3 weeks.

[0293] In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are administered about every 3-4 weeks. In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are administered about every 4 weeks. In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are administered about every 3 weeks.

[0294] BNT ref. [P1955WO01] / / C&F ref. [241010WO] In some embodiments, the anti-CTLA4 antibody and / or the anti-PD-1 antibody are administered on the first day of each treatment cycle. In some embodiments, the anti- CTLA4 antibody and the anti-PD-1 antibody are administered on the first day of each treatment cycle.

[0295] In some embodiments, the anti-CTLA4 antibody dosage administered ranges from about 0.1 mg / kg to about 2.9 mg / kg body weight, optionally from about 0.5 mg / kg to about 2.9 mg / kg body weight, optionally from about 0.5 mg / kg to about 2.5 mg / kg body weight, and optionally from about 1 mg / kg to about 2 mg / kg body weight.

[0296] In some embodiments, the anti-CTLA4 antibody dosage administered can be independently selected from about 0.1 mg / kg body weight, about 0.3 mg / kg body weight, about 0.5 mg / kg body weight, about 1.0 mg / kg body weight, about 1.5 mg / kg body weight, about 2.0 mg / kg body weight, about 2.5 mg / kg body weight, and about 2.9 mg / kg body weight. In some embodiments, the anti-CTLA4 antibody dosage administered can be independently selected from about 1 mg / kg body weight and about 2 mg / kg body weight.

[0297] In some embodiments, the anti-CTLA4 antibody is administered at a dosage of about 0.5 mg / kg body weight. In some embodiments, the anti-CTLA4 antibody is administered at a dosage of 1 mg / kg body weight. In some embodiments, the anti-CTLA4 antibody is administered at a dosage of about 2 mg / kg body weight.

[0298] The subject afflicted with cancer and treated with the anti-CTLA4 antibody disclosed herein can suffer from treatment-related adverse events, e.g., from irAEs. For example, the subject afflicted with cancer and treated with the anti-CTLA4 antibody disclosed herein may suffer from severe skin reactions or other grade 3 or 4 non-hematological toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. In such cases, the dose of the anti-CTLA4 antibody can be reduced.

[0299] In some embodiments, the anti-PD-1 antibody dosage can be a fixed dosage. In some embodiments, the anti-PD-1 antibody dosage administered ranges from about 175 to about

[0300] BNT ref. [P1955WO01] / / C&F ref. [241010WO] 225 mg. In some embodiments, the anti-PD-1 antibody dosage administered is about 200 mg.

[0301] In some embodiments, the anti-CTLA4 antibody is administered at a dosage of about 1 or 2 mg / kg body weight, and the anti-PD-1 antibody dosage is administered at a dosage of about 200 mg.

[0302] In some embodiments, the subject has been previously treated for cancer, in particular the subject has had at least one previous chemotherapy treatment. In some embodiments, the at least one previous chemotherapy treatment comprises or is a platinum-containing chemotherapy. In some embodiments, the platinum-containing chemotherapy comprises or is selected from satraplatin, cisplatin, carboplatin, nedaplatin, lobaplatin, or combinations thereof.

[0303] In some embodiments, the platinum-containing chemotherapy comprises a further chemotherapeutic agent, optionally wherein the further chemotherapeutic agent is paclitaxel or docetaxel. For example, the previous chemotherapy treatment can comprise cisplatin and paclitaxel or carboplatin and paclitaxel.

[0304] In some embodiments, the subject has been previously treated with bevacizumab. In some embodiments, the subject has not been previously treated with bevacizumab. Bevacizumab (Avastin® - Genentech / Roche) is a humanized monoclonal antibody that recognizes and blocks vascular endothelial growth factor (VEGF). VEGF is a chemical signal that stimulates the growth of new blood vessels (angiogenesis). This antibody and its preparation are disclosed in US 6,054,297.

[0305] In some embodiments, overall survival is increased in a subject afflicted with cancer compared to an anti-PD-1 antibody treatment, such as pembrolizumab treatment, alone. In some embodiments, overall survival is increased in a subject afflicted with cancer compared to an anti-CTLA4 antibody treatment. In some embodiments, overall survival is increased in a subject afflicted with cancer compared to an ipilimumab and nivolumab combination treatment. In some embodiments, the median progression-free survival is

[0306] BNT ref. [P1955WO01] / / C&F ref. [241010WO] increased in a subject afflicted with cancer compared to an anti-PD-1 antibody treatment, such as pembrolizumab treatment, alone. In some embodiments, median progression-free survival is increased in a subject afflicted with cancer compared to an anti-CTLA4 antibody treatment. In some embodiments, median progression-free survival is increased in a subject afflicted with cancer compared to an ipilimumab and nivolumab combination treatment.

[0307] In some embodiments, the platinum-resistant ovarian cancer to be treated by the combination of the present disclosure is selected from high-grade serous ovarian cancer, primary peritoneal cancer, and fallopian tube cancer. In some embodiments, the platinum- resistant ovarian cancer to be treated is high-grade serous ovarian cancer. In some embodiments, the platinum-resistant ovarian cancer to be treated is primary peritoneal cancer. In some embodiments, the platinum-resistant ovarian cancer to be treated is fallopian tube cancer.

[0308] The anti-CTLA4 antibody and the anti-PD-1 antibody provided herein can be administered via any suitable route of administration, e.g., parenteral route of administration. “Parenteral route” of administration refers to a route of administration other than enteral route.

[0309] Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumor, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal, subcutaneous, or topical administration.

[0310] The anti-CTLA4 antibody and the anti-PD-1 antibody of the present disclosure can be administered using any suitable method. The suitable route and method of administration may vary depending on a number of factors such as the specific therapeutic agent being used, the rate of absorption desired, specific formulation or dosage form used, type or severity of the disorder being treated, the specific site of action, and conditions of the subject, and can be readily selected by a person skilled in the art. Administration can be systemic or local.

[0311] In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody may be administered intravenously, intraarterially, subcutaneously, intradermally, dermally,

[0312] BNT ref. [P1955WO01] / / C&F ref. [241010WO] intranodally, or intramuscularly. In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are formulated for local administration or systemic administration. Systemic administration may include enteral administration, which involves absorption through the gastrointestinal tract, or parenteral administration. In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are formulated for systemic administration. In some embodiments, the systemic administration is by intravenous administration. In some embodiments, the anti-CTLA4 and the anti-PD-1 antibody are formulated for intravenous administration.

[0313] In some embodiments, the anti-CTLA4 antibody and / or the anti-PD-1 antibody are administered intravenously. In some embodiments, the anti-CTLA4 antibody and the anti- PD-1 antibody are administered intravenously. In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are administered via an intravenous injection or an intravenous infusion. In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are administered via an intravenous infusion.

[0314] In some embodiments, the anti-CTLA4 antibody and the anti-PD-1 antibody are formulated with one or more pharmaceutically acceptable carriers, diluents and / or excipients.

[0315] Suitable carriers include, for example, sterile water, Ringer, Ringer lactate, sterile sodium chloride solution, isotonic saline, polyalkylene glycols, hydrogenated naphthalenes and, in particular, biocompatible lactide polymers, lactide / glycolide copolymers or polyoxyethylene / polyoxy-propylene copolymers. Suitable carriers for parenteral administration are preferably isotonic to the blood of the recipient. Non-limiting examples of suitable diluents include ethanol, glycerol, and water. Examples of excipients include without limitation carriers, binders, diluents, lubricants, thickeners, surface active agents, preservatives, stabilizers, emulsifiers, buffers, flavoring agents, or colorants.

[0316] BNT ref. [P1955WO01] / / C&F ref. [241010WO] The composition and kit of parts

[0317] The disclosure further provides a composition comprising an anti-CTLA4 antibody, wherein the composition is for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) an anti-PD-1 antibody (such a pembrolizumab), wherein the anti-CTLA4 antibody comprises:

[0318] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0319] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0320] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in

[0321] BNT ref. [P1955WO01] / / C&F ref. [241010WO] SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0322] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0323] In some embodiments, the anti-CTLA4 antibody has been diluted with 5% Dextrose Solution to a final concentration of about 0.5 to about 3.0 mg / mL. In some embodiments, the anti-CTLA4 antibody has been diluted with 5% Dextrose Solution to a final concentration of about 0.5 to about 3.0 mg / mL from a formulation containing 30 mg / mL anti-CTLA-4 antibody, 20 mM histidine buffer, 8.8% (w / v) trehalose dihydrate, and 0.06% (w / v) PS80 at pH 6.0.

[0324] In some embodiments, the anti-CTLA4 antibody disclosed herein is formulated in 20 mM histidine buffer, 8.8% (w / v) trehalose dihydrate, and 0.06% (w / v) PS80 at pH 6.0, wherein in some embodiments the concentration of the anti-CTLA4 antibody can be in a certain range e.g. 2.5 to 50 mg / mL, preferably 5 to 45 mg / mL, more preferably 10 to 40 mg / mL, even more preferably 15 to 40 mg / mL, even more preferably 20 to 40 mg / mL, even more preferably 25 to 35 mg / mL, even more preferably 27.5 to 32.5 mg / mL, and most preferably 30 mg / mL.

[0325] In some embodiments, the anti-CTLA4 antibody has been diluted with 5% Dextrose Solution to a final concentration of about 0.5 to about 3.0 mg / mL from a formulation coprising 20 mM histidine buffer, 8.8% (w / v) trehalose dihydrate, and 0.06% (w / v) PS80 at pH 6.0, wherein in some embodiments the concentration of the anti-CTLA4 antibody can be in a certain range e.g. 2.5 to 50 mg / mL, preferably 5 to 45 mg / mL, more preferably 10 to

[0326] BNT ref. [P1955WO01] / / C&F ref. [241010WO] 40 mg / mL, even more preferably 15 to 40 mg / mL, even more preferably 20 to 40 mg / mL, even more preferably 25 to 35 mg / mL, even more preferably 27.5 to 32.5 mg / mL, and most preferably 30 mg / mL.

[0327] In some embodiments, the composition comprises: a) the anti-CTLA4 antibody disclosed herein, b) about 20 mM histidine buffer, c) about 8.8% (w / v) trehalose dihydrate, and d) about 0.06% (w / v) PS80, at pH 6.0, wherein in some embodiments the concentration of the anti-CTLA-4 antibody can be 2.5 to 50 mg / mL, preferably 5 to 45 mg / mL, more preferably 10 to 40 mg / mL, even more preferably 15 to 40 mg / mL, even more preferably 20 to 40 mg / mL, even more preferably 25 to 35 mg / mL, even more preferably 27.5 to 32.5 mg / mL, and most preferably 30 mg / mL.

[0328] The pH is preferably measured at 22 °C. The disclosure further provides a composition comprising an anti-PD-1 antibody (such a pembrolizumab), wherein the composition is for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) an anti-CTLA4 antibody; and b) the anti-PD-1 antibody (such a pembrolizumab), wherein the anti-CTLA4 antibody comprises:

[0329] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in

[0330] BNT ref. [P1955WO01] / / C&F ref. [241010WO] SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0331] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6 wherein the anti-PD-1 antibody comprises:

[0332] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0333] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0334] The embodiments disclosed herein for the method of treatment comprising the anti-CTLA4 antibody in combination with the anti-PD-1 antibody can be used in the composition as disclosed herein. Features described herein in more detail in connection with the “anti-

[0335] BNT ref. [P1955WO01] / / C&F ref. [241010WO] CTLA4 antibody for use in a method of treating, the anti-PD-1 antibody for use in a method of treating, or the anti-CTLA4 antibody and the anti-PD-1 antibody for use in a method of treating” embodiments equally apply to the corresponding composition embodiments.

[0336] In some embodiments, the composition comprises an additional immunomodulatory agent.

[0337] In some embodiments, the composition comprises one or more pharmaceutically acceptable carriers, diluents and / or excipients.

[0338] In some embodiments, the composition is a pharmaceutical composition. In some preferred embodiments, the anti-CLTA4 antibody and the anti-PD-1 antibody are comprised in individual pharmaceutical compositions. For example, the anti-CLTA4 antibody and the anti-PD-1 antibody of the present disclosure are comprised in two different pharmaceutical compositions, each individually comprising the anti-CLTA4 antibody or the anti-PD-1 antibody.

[0339] The disclosure further provides a kit of parts comprising: a) an anti-CTLA4 antibody disclosed herein; and b) an anti-PD-1 antibody disclosed herein.

[0340] The embodiments disclosed herein for the method of treatment comprising the anti-CTLA4 antibody in combination with the anti-PD-1 antibody can be used in the kit of parts as disclosed herein. Features described herein in more detail in connection with the “anti- CTLA4 antibody for use in a method of treating, an anti-PD-1 antibody for use in a method of treating, or the anti-CTLA4 antibody and the anti-PD-1 antibody for use in a method of treating” embodiments equally apply to the corresponding kit of parts embodiments.

[0341] In some embodiments, the kit of parts comprises an additional immunomodulatory agent.

[0342] BNT ref. [P1955WO01] / / C&F ref. [241010WO] In some embodiments, the kit of parts comprises one or more containers comprising the anti-CTLA4 antibody and the anti-PD-1 antibody. In some embodiments, the kit of parts comprises individual containers, each individually comprising the anti-CTLA4 antibody and the anti-PD-1 antibody.

[0343] The method of treatment

[0344] The invention also provides method of treating platinum -resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) an anti-CTLA4 antibody; and b) an anti-PD-1 antibody (such a pembrolizumab), wherein the anti-CTLA4 antibody comprises:

[0345] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and

[0346] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:

[0347] BNT ref. [P1955WO01] / / C&F ref. [241010WO] (i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and

[0348] (ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

[0349] The embodiments disclosed herein for the method of treatment comprising the anti-CTLA4 antibody in combination with the anti-PD-1 antibody can be used in the method of treating as disclosed herein. Features described herein in more detail in connection with the above described “anti-CTLA4 antibody for use in a method of treating platinum-resistant ovarian cancer, the anti-PD-1 antibody for use in a method of treating platinum -resistant ovarian cancer, or the anti-CTLA4 antibody and the anti-PD-1 antibody for use in a method of treating platinum-resistant ovarian cancer” embodiments equally apply to the corresponding method of treating platinum-resistant ovarian cancer embodiments.

[0350] SEQUENCE LISTING

[0351] This application contains a Sequence Listing which has been submitted electronically and is hereby incorporated by reference in its entirety. Said Sequence Listing file is named 241010WO_Sequence Listing.xml and 26.286 Bytes in size.

[0352] SEQ ID NOs: 1-6 are exemplary amino acid sequences of heavy and light chain CDR1-3 sequences of the anti-CTLA4 antibody.

[0353] BNT ref. [P1955WO01] / / C&F ref. [241010WO] SEQ ID NOs: 7 and 8 are exemplary amino acid sequences of heavy and light chain variable domain of the anti-CTLA4 antibody.

[0354] SEQ ID NO: 9 is an exemplary amino acid sequence of a mutated Fc region suitable for the anti-CTLA4 antibody.

[0355] SEQ ID NO: 10 and 12 are exemplary amino acid sequences of the full-length heavy and light chain of the anti-CTLA4 antibody.

[0356] SEQ ID NOs: 11 and 13 are exemplary polynucleotide sequences of the full-length heavy and light chain of the anti-CTLA4 antibody.

[0357] SEQ ID NO: 14 is an exemplary amino acid sequence of an unmutated Fc region.

[0358] SEQ ID NOs: 15-20 are exemplary amino acid sequences of heavy and light chain CDR1-3 sequences of the anti-PD-1 antibody.

[0359] SEQ ID NOs: 21 and 22 are exemplary amino acid sequences of heavy and light chain variable domain of the anti-PD-1 antibody.

[0360] SEQ ID NO: 23 and 24 are exemplary amino acid sequences of the full-length heavy and light chain of the anti-PD-1 antibody.

[0361] EXAMPLES

[0362] A clinical study was performed to investigate the therapeutic effect of using the combination of the anti-CTLA-4 antibody (the anti-CTLA4 antibody disclosed herein comprising heavy and light chains of SEQ ID NO: 10 and 12) and pembrolizumab in the treatment of ovarian cancer in patients with platinum -resistant, high grade, serious ovarian cancer. The patients were: i) female adults over the age of 18, ii) which had a prior hysterectomy and salpingo- oophorectomy; iii) had one or more systemic platinum-based therapies; iv) are platinum resistant; v) have RECIST 1.1 measurable lesions; and vi) have an Eastern Cooperative

[0363] BNT ref. [P1955WO01] / / C&F ref. [241010WO] Oncology Group (ECOG) score of 0-1. The patients were randomized 1 : 1 into the following groups:

[0364] • Group 1 (anti-CTLA4 antibody and pembrolizumab combination therapy): The anti- CTLA4 antibody and pembrolizumab were administered concurrently for a Q3 week schedule (21 days) for up to 35 treatment cycles. During treatment cycles the anti- CTLA4 antibody was administered at 1 mg / kg and the pembrolizumab was administered at 200mg.

[0365] • Group 2 (anti-CTLA4 antibody and pembrolizumab combination therapy): The anti- CTLA4 antibody and pembrolizumab were administered intravenously concurrently for a Q3 week schedule (21 days) for up to 35 treatment cycles. During treatment cycles the anti-CTLA4 antibody was administered at 2 mg / kg and the pembrolizumab was administered at 200mg.

[0366] 83 patients had received >1 dose of the anti-CTLA4 antibody + pembrolizumab with 33 and 29 patients in 1 mg / kg and 2 mg / kg the anti-CTLA4 antibody + pembrolizumab groups, respectively. At the safety and efficacy cutoff date with a median follow-up of 2.1 months (range 0.1-9.2), grade >3 treatment-related adverse events (TRAEs) were observed in 35.7% and 31.0% patients in 1 mg / kg or 2 mg / kg groups, respectively. No grade 5 TRAEs were observed. Common grade 3 TRAEs from combined groups were increased alanine transaminase (ALT) and aspartate transaminase (AST) (both 7.0%), and diarrhea (5.3%). Unconfirmed ORR was 31.8% (7 / 22; 95% CI 13.9-54.9) and 36.4% (8 / 22; 95% CI 17.2- 59.3) in 1 mg / kg and 2 mg / kg groups, respectively (see Table 3).

[0367] Table 3: Summary of safety and efficacy data

[0368] BNT ref. [P1955WO01] / / C&F ref. [241010WO]

[0369] The results surprisingly show an effective and safe treatment and an unexpected beneficial effect with the objective response rate (ORR) (per RECIST 1.1) equal to or greater than 25% in both Group 1 and Group 2 in this difficult to treat patient population. The average treatment duration in these patients has been about three months with three treatment cycles administered to date. These data demonstrates that the combination therapy comprising the anti-CTLA4 antibody and pembrolizumab is particularly suitable for the treatment ovarian cancer patients with platinum-resistant, high grade, serious ovarian cancer.

[0370] Table 4: PK-results

[0371] BNT ref. [P1955WO01] / / C&F ref. [241010WO] The pK parameters corresponding to the Img / kg and 2mg / kg dosages of the CTLA4 antibody (comprising heavy and light chains of SEQ ID NO: 10 and 12) were measured after administration in combination with 200mg of pembrolizumab once every 3 weeks (Q3W). The pK parameters (C max, Cmin, and AUC) increased proportionally with dose escalation (see Table 4). These data show that the pK of the CTLA4 antibody, when administered in combination with 200mg of pembrolizumab, is comparable to the pK of the CTLA4 antibody monotherapy thereby showing a lack of pembrolizumab effect on the PK.

[0372] The intermediate Overall Survival results of the clinical trial, as shown in Figure 2, demonstrated an unexpected improvement in Overall Survival in the 1 mg / kg of the anti- CTLA4 antibody + 200mg pembrolizumab Q3W (Group 1) compared to the 2 mg / kg of the anti-CTLA4 antibody + 200mg pembrolizumab Q3W (Group 2) patients with platinum- resistant ovarian cancer (PROC).

[0373] Demographics and Baseline Characteristics of those patients participating in the Clinical Trial of this example is shown in Table 6 below. The data is displayed in two dosing groups: i) PROC patients who received the anti-CTLA-4 antibody at a lower dose (1 mg / kg Q3W plus 200mg pembrolizumab Q3W); and ii) PROC patients who received the anti- CTLA-4 antibody at a higher dose (2 mg / kg Q3W plus 200mg pembrolizumab Q3W).

[0374] As shown in Figure 2 and Table 5, the Overall Survival (OS) improves upon the lower dosing of the anti-CTLA-4 antibody treatment compared to higher dosing of the anti- CTLA-4 antibody treatment (mOS: non-evaluable (NE) vs 8.28 months) for PROC with curves separating starting at 4 months after randomization. Table 5 shows a statistical summary of the results of Figure 2, including a percentage of Overall Survival at greater than three (3), six (6), twelve (12) and eighteen (18) months since randomization.

[0375] BNT ref. [P1955WO01] / / C&F ref. [241010WO] Table 5: Overall Survival of Efficacy Evaluable Set of Patients

[0376] Demographics and Baseline Characteristics of those patients participating in the Clinical Trial of the examples are shown in Table 6 below.

[0377] Table 6: Demographics and Baseline Characteristics of Efficacy Evaluable Set of Patients

[0378] BNT ref. [P1955WO01] / / C&F ref. [241010WO]

[0379] BRIEF DESCRIPTION OF THE DRAWINGS

[0380] Figure 1 depicts the full-length light chain (SEQ ID NO:24) and the full-length heavy chain (SEQ ID NO:23) amino acid sequences of the anti-PD-1 antibody pembrolizumab. The full-length light chain amino acid sequence comprises the CDR1, CDR2, and CDR3 sequences (SEQ IDs NO: 18-20) of pembrolizumab in N- to C-terminal orientation (highlighted in boxes). The full-length heavy chain amino acid sequence comprises the CDR1, CDR2, and CDR3 sequences (SEQ IDs NO: 15-17) of pembrolizumab in N- to C- terminal orientation (highlighted in boxes). The variable domain sequences of the light chain (SEQ ID NO: 22) and the heavy chain (SEQ ID NO: 21) of pembrolizumab are underlined.

[0381] Figure 2 depicts Kaplan-Meier Curves of Overall Survival of the two dose groups: 1 mg / kg of the anti-CTLA4 antibody Q3W + 200 mg pembrolizumab Q3W (Group 1); and 2 mg / kg of the anti-CTLA4 antibody Q3W + 200 mg pembrolizumab (Group 2).

[0382] BNT ref. [P1955WO01] / / C&F ref. [241010WO]

Claims

C l a i m s1. An anti-CTLA4 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) an anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:(i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and(ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:(i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set1BNT ref. [P1955WO01] / / C&F ref. 241010WOforth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and(ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

2. The anti-CTLA4 antibody for use according to claim 1, wherein the anti-CTLA4 antibody and the anti-PD-1 antibody are administered separately.

3. The anti-CTLA4 antibody for use according to any of claim 1 or 2, wherein the anti- CTLA4 antibody and the anti-PD-1 antibody are administered concurrently or consecutively, optionally wherein the anti-CTLA4 antibody and the anti-PD-1 antibody are administered consecutively.

4. The anti-CTLA4 antibody for use according to any of claims 1-3, wherein the anti- CTLA4 antibody and the anti-PD-1 antibody are administered intravenously.

5. The anti-CTLA4 antibody for use according to any of claims 1-4, wherein the anti- CTLA4 antibody and the anti-PD-1 antibody are administered via an intravenous injection or an intravenous infusion, optionally an intravenous infusion.

6. The anti-CTLA4 antibody for use according to any of claims 1-5, wherein the anti- CTLA4 antibody dosage administered ranges from about 0.1 mg / kg to about 2.9BNT ref. [P1955WO01] / / C&F ref. [241010WO]mg / kg body weight, optionally from about 0.5 mg / kg to about 2.9 mg / kg body weight, optionally from about 0.5 mg / kg to about 2.5 mg / kg body weight, optionally from about 1 mg / kg to about 2 mg / kg body weight.

7. The anti-CTLA4 antibody for use according to any of claims 1-6, wherein the anti- CTLA4 antibody dosage administered is independently selected from about 0.1 mg / kg body weight, about 0.3 mg / kg body weight, about 0.5 mg / kg body weight, about 1 mg / kg body weight, about 1.5 mg / kg body weight, about 2 mg / kg body weight, about 2.5 mg / kg body weight, and about 2.9 mg / kg body weight, , optionally wherein the anti-CTLA4 antibody dosage administered is independently selected from about 1 mg / kg body weight and about 2 mg / kg body weight.

8. The anti-CTLA4 antibody for use according to any of claims 1-7, wherein the anti- PD-1 antibody dosage administered ranges from about 175 to about 225 mg.

9. The anti-CTLA4 antibody for use according to any of claims 1-8, wherein the anti- PD-1 antibody dosage administered is about 200 mg.

10. The anti-CTLA4 antibody for use according to any of claims 1-9, wherein a treatment cycle is repeated at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 times, optionally at least 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33 or 35 times.

11. The anti-CTLA4 antibody for use according to any of claims 1-10, wherein each treatment cycle has up to about 18 to about 28 days, optionally 18 to about 24 days.

12. The anti-CTLA4 antibody for use according to any of claims 1-11, wherein the anti- CTLA4 antibody is administered about every 4 weeks, optionally about every 3 weeks.BNT ref. [P1955WO01] / / C&F ref. [241010WO]13. The anti-CTLA4 antibody for use according to any of claims 1-12, wherein the anti- PD-1 antibody is administered about every 4 weeks, optionally about every 3 weeks.

14. The anti-CTLA4 antibody for use according to any of claims 1-13, wherein the anti- CTLA4 antibody and / or the anti-PD-1 antibody are administered for 17 to 35 treatment cycles or up to 1 to 2 years, optionally 35 treatment cycles or up to 2 years.

15. The anti-CTLA4 antibody for use according to any of claims 1-14, wherein the anti- CTLA4 antibody and / or the anti-PD-1 antibody are formulated with one or more pharmaceutically acceptable carriers, diluents and / or excipients.

16. The anti-CTLA4 antibody for use according to any of claims 1-15, wherein the subject has been previously treated for cancer, optionally wherein the subject had at least one previous chemotherapy treatment.

17. The anti-CTLA4 antibody for use according to claim 16, wherein the at least one previous chemotherapy treatment comprises or is a platinum-containing chemotherapy treatment.

18. The anti-CTLA4 antibody for use according to any of claims 1-17, wherein the subject has been previously treated with bevacizumab.

19. The anti-CTLA4 antibody for use according to any of claims 1-18, wherein overall survival is increased in said subject compared to the anti-PD-1 antibody treatment alone.

20. The anti-CTLA4 antibody for use according to any of claims 1-19, wherein median progression-free survival is increased in said subject compared to the anti-PD-1 antibody treatment alone.BNT ref. [P1955WO01] / / C&F ref. [241010WO]21. The anti-CTLA4 antibody for use according to any of claims 1-20, wherein the platinum-resistant ovarian cancer is selected from high-grade serous ovarian cancer, primary peritoneal cancer, and fallopian tube cancer.

22. The anti-CTLA4 antibody for use according to any of claims 1-21, wherein the platinum-containing chemotherapy comprises or is selected from satraplatin, cisplatin, carboplatin, nedaplatin, lobaplatin or combinations thereof.

23. The anti-CTLA4 antibody for use according to any of claims 1-22, wherein the platinum-containing chemotherapy comprises a further chemotherapeutic agent, optionally wherein the further chemotherapeutic agent is paclitaxel or docetaxel.

24. The anti-CTLA4 antibody for use according to any of claims 1-23, wherein the subject has previously not been treated with bevacizumab.

25. The anti-CTLA4 antibody for use according to any of claims 1-24, wherein the anti- CTLA4 antibody comprises: a) a heavy chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 7; and b) a light chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 8, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 8.

26. The anti-CTLA4 antibody for use according to any of claims 1-25, wherein the anti- CTLA4 antibody comprises an IgGl Fc, preferably comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 9 or an amino acid sequence comprising at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9.BNT ref. [P1955WO01] / / C&F ref. [241010WO]27. The anti-CTLA4 antibody for use according to any of claims 1-26, wherein the anti- CTLA4 antibody comprises: a) a heavy chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 10, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10; and b) a light chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 12 or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 12.

28. The anti-CTLA4 antibody for use according to any of claims 1-27, wherein the anti- CTLA4 antibody is capable of binding to human CTLA4.

29. The anti-CTLA4 antibody for use according to any of claims 1-28, wherein the anti- CTLA4 antibody is a humanized anti-CTLA4 antibody.

30. The anti-CTLA4 antibody for use according to any of claims 1-29, wherein the subject is a human.

31. The anti-CTLA4 antibody for use according to claims 1-30, wherein the anti-CTLA4 antibody and / or the anti-PD-1 antibody are administered on the first day of each treatment cycle.

32. The anti-CTLA4 antibody for use according to any of claims 1-31, wherein the anti- PD-1 antibody comprises: a) a heavy chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 21 or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 21; andBNT ref. [P1955WO01] / / C&F ref. [241010WO]b) a light chain variable domain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 22, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 22.

33. The anti-CTLA4 antibody for use according to any of claims 1-32, wherein the anti- PD-1 antibody comprises: a) a heavy chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 23, or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 23; and b) a light chain comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 24 or an amino acid sequence comprising at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 24.

34. The anti-CTLA4 antibody for use according to any of claims 1-33, wherein the anti- PD-1 antibody is pembrolizumab.

35. An anti-CTLA4 antibody and an anti-PD-1 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) the anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:(i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence setBNT ref. [P1955WO01] / / C&F ref. [241010WO]forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and(ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:(i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and(ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.BNT ref. [P1955WO01] / / C&F ref. [241010WO]36. A method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) an anti-CTLA4 antibody; and b) an anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:(i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and(ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:(i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3)BNT ref. [P1955WO01] / / C&F ref. [241010WO]comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and(ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

37. A composition comprising an anti-CTLA4 antibody for use in a method of treating platinum-resistant ovarian cancer in a subject in need thereof, wherein the method comprises administering to the subject: a) the anti-CTLA4 antibody; and b) an anti-PD-1 antibody, wherein the anti-CTLA4 antibody comprises:(i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 1, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 2, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 3; and(ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 4, (2) a complementarity-determining region 2 (LCDR2)BNT ref. [P1955WO01] / / C&F ref. [241010WO]comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 5, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 6; wherein the anti-PD-1 antibody comprises:(i) a heavy chain variable region comprising (1) a complementarity-determining region 1 (HCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 15, (2) a complementarity-determining region 2 (HCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 16, and (3) a complementarity-determining region 3 (HCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 17; and(ii) a light chain variable region comprising (1) a complementarity-determining region 1 (LCDR1) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 18, (2) a complementarity-determining region 2 (LCDR2) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 19, and (3) a complementarity-determining region 3 (LCDR3) comprising or consisting of an amino acid sequence set forth in SEQ ID NO: 20.

38. The composition of claim 37, wherein the anti-CTLA-4 antibody has been diluted with 5% Dextrose Solution to a final concentration of about 0.5 to about 3.0 mg / mL, from a formulation containing 30 mg / mL anti-CTLA-4 antibody, 20 mM histidine buffer, 8.8% (w / v) trehalose dihydrate, and 0.06% (w / v) PS80 at pH 6.0.

39. The composition according to any of claim 37 or 38, wherein the composition is a pharmaceutical composition.BNT ref. [P1955WO01] / / C&F ref. [241010WO]0. The composition according to any of claims 37-39, wherein the composition comprises one or more pharmaceutically acceptable carriers, diluents and / or excipients.BNT ref. [P1955WO01] / / C&F ref. [241010WO]

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