Pharmaceutical compositions of B7-H3 antibodies and uses thereof

Abstract

The present invention provides pharmaceutical compositions comprising an anti-human B7-H3 ("hB7-H3") antibody ("enoblituzumab") and a buffer for storage and administration. The present invention provides containers and kits comprising the pharmaceutical compositions. The present invention further provides uses of the pharmaceutical compositions, containers, and kits containing enoblituzumab for the treatment of cancer, and in certain embodiments, for the treatment of cancers that express B7-H3.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 63 / 222,750 (filed July 16, 2021; pending), which is incorporated by reference in its entirety into this application.

[0002] Sequence Listing Reference This application contains one or more sequence listings in accordance with Title 37, Code of Federal Regulations, Sections 1.821 et seq., which are disclosed in a computer-readable medium (Filename: 1301_0169PCT_TW.xml, created on June 2, 2022, size: 4,307 bytes), which file is incorporated by reference in its entirety into this application.

[0003] Technical Field The present invention provides pharmaceutical compositions comprising an anti-human B7-H3 ("hB7-H3") antibody ("enoblituzumab") and a buffer for storage and administration. The present invention further provides containers and kits comprising the pharmaceutical compositions. The present invention further provides uses of the pharmaceutical compositions, containers, and kits containing enoblituzumab for the treatment of cancer, and in certain embodiments, for the treatment of cancers that express B7-H3. [Background technology]

[0004] B7-H3 (also known as "CD276") is expressed on antigen-presenting cells and binds to one or more unspecified receptors to mediate co-inhibition of T cells. Furthermore, B7-H3 acts as an inhibitor of NK cells and osteoblasts through interaction with one or more unknown receptors (Non-Patent Document 1). B7-H3 is expressed on a variety of cancer cells (e.g., neuroblastoma, gastric cancer, ovarian cancer, non-small cell lung cancer, etc.) (see, for example, Non-Patent Document 2). The role of B7-H3 in inhibiting the immune system and the increased expression of B7-H3 on human tumors suggest that this molecule may serve as a therapeutic target for the treatment of cancer. Anti-hB7-H3 antibodies and other molecules that modulate B7-H3 expression have been reported to be used to treat tumors and / or upregulate immune responses (see, for example, Patent Document 1). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 8,802,091 [Non-patent literature]

[0006] [Non-Patent Document 1] Hofmeyer, K. et al. (2008) “The Contrasting Role Of B7-H3,” Proc. Natl. Acad. Sci. (USA) 105(30):10277-10278 [Non-Patent Document 2] Modak, S., et al. (2001) “monoclonal antibody 8H9 targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors,” Cancer Res 61:4048-54 Summary of the Invention [Problem to be solved by the invention]

[0007] In certain aspects, the invention provides pharmaceutical compositions for patients with tumors that express B7-H3, including patients with tumors that express low levels of B7-H3 or who have failed other treatments. The invention further provides pharmaceutical compositions comprising enoblituzumab. The invention further provides uses of such pharmaceutical compositions and pharmaceutical kits containing such pharmaceutical compositions, e.g., for treating cancer with a therapeutically or prophylactically effective amount of enoblituzumab, and in certain aspects, for treating cancers that express B7-H3. [Means for solving the problem]

[0008] In one embodiment, the present invention provides a pharmaceutical composition that maintains the stability of enoblitutuzumab over a broad concentration range of about 5 mg / mL to about 200 mg / mL, including relatively low concentrations (e.g., about 5 mg / mL to about 60 mg / mL) and relatively high concentrations (e.g., about 60 mg / mL to about 200 mg / mL).The present invention further provides a pharmaceutical composition comprising enoblitutuzumab, acetate, sucrose, polysorbate 80 ("PS80"), and water.

[0009] The present invention provides an embodiment of the aforementioned pharmaceutical composition, wherein the acetate salt has a concentration of about 5 mM to about 30 mM.The present invention further provides an embodiment of the aforementioned pharmaceutical composition, wherein the acetate salt comprises sodium acetate.The present invention provides an embodiment of the aforementioned pharmaceutical composition, wherein the acetate salt comprises glacial acetic acid and sodium acetate.

[0010] The present invention relates to a composition comprising: a) about 5 mM to about 30 mM acetate, about 50 mg / mL to about 130 mg / mL sucrose, about 0.05 mg / mL to about 0.6 mg / mL PS80, and water, wherein the pH of the composition is about 4.0 to about 6.0; or b) about 8 mM to about 24 mM acetate, about 72 mg / mL to about 108 mg / mL sucrose, about 0.05 mg / mL to about 0.6 mg / mL PS80, and water, wherein the pH of the composition is about 4.4 to about 5.6; or c) about 16 mM to about 24 mM acetate, about 72 mg / mL to about 108 mg / mL sucrose, about 0.05 mg / mL to about 0.2 mg / mL PS80, and water, wherein the pH of the composition is about 4.3 to about 5.3; or d) about 8 mM to about 12 mM acetate, about 72 mg / mL to about 108 mg / mL sucrose, about 0.05 mg / mL to about 0.2 mg / mL PS80, and water, wherein the pH of the composition is about 4.5 to about 5.5; or e) about 10 mM acetate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, wherein the pH of the composition is about 4.6 to about 5.5; or f) An embodiment of the pharmaceutical composition as described above is provided, comprising about 20 mM acetate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, wherein the pH of the composition is about 4.4 to about 5.2.

[0011] The present invention provides an embodiment of the above-described pharmaceutical composition, wherein the acetate comprises glacial acetic acid at a concentration of about 0.1 mg / mL to about 0.65 mg / mL and sodium acetate trihydrate at a concentration of about 0.6 mg / mL to about 1.8 mg / mL.

[0012] The present invention provides an embodiment of the pharmaceutical composition described above, wherein the concentration of the enoblituzumab is about 5 mg / mL to about 60 mg / mL.The present invention further provides an embodiment of the pharmaceutical composition described above, wherein the concentration of the enoblituzumab is about 20 mg / mL to about 30 mg / mL.The present invention further provides an embodiment of the pharmaceutical composition described above, wherein the concentration of the enoblituzumab is about 25 mg / mL.

[0013] The present invention provides an embodiment of the above-mentioned pharmaceutical composition, wherein the acetate comprises glacial acetic acid at a concentration of about 0.1 mg / mL to about 0.35 mg / mL and sodium acetate trihydrate at a concentration of about 0.60 mg / mL to about 1.2 mg / mL.The present invention further provides an embodiment of the above-mentioned pharmaceutical composition, wherein the acetate comprises glacial acetic acid at a concentration of about 0.18 mg / mL and sodium acetate trihydrate at a concentration of about 0.95 mg / mL.The present invention further provides an embodiment of the above-mentioned pharmaceutical composition, wherein the acetate comprises glacial acetic acid at a concentration of about 0.27 mg / mL and sodium acetate trihydrate at a concentration of about 0.74 mg / mL.

[0014] The present invention provides an embodiment of the pharmaceutical composition described above, wherein the concentration of the enoblituzumab is about 90 mg / mL to about 200 mg / mL.The present invention further provides an embodiment of the pharmaceutical composition described above, wherein the concentration of the enoblituzumab is about 120 mg / mL.

[0015] The present invention provides an embodiment of the above-mentioned pharmaceutical composition, wherein the acetate comprises glacial acetic acid at a concentration of about 0.4 mg / mL to about 0.65 mg / mL and sodium acetate trihydrate at a concentration of about 1.2 mg / mL to about 1.8 mg / mL.The present invention further provides an embodiment of the above-mentioned pharmaceutical composition, wherein the acetate comprises glacial acetic acid at a concentration of about 0.52 mg / mL and sodium acetate trihydrate at a concentration of about 1.5 mg / mL.

[0016] The present invention provides an embodiment of the above-mentioned pharmaceutical composition, wherein the sucrose is present in a concentration of about 50 mg / mL to about 130 mg / mL.The present invention further provides an embodiment of the above-mentioned pharmaceutical composition, wherein the sucrose is present in a concentration of about 72 mg / mL to about 108 mg / mL.The present invention further provides an embodiment of the above-mentioned pharmaceutical composition, wherein the concentration of the sucrose is about 90 mg / mL.

[0017] The present invention provides an embodiment of the above-mentioned pharmaceutical composition, wherein the PS80 is present at a concentration of about 0.05 mg / mL to about 0.6 mg / mL.The present invention further provides an embodiment of the above-mentioned pharmaceutical composition, wherein the PS80 is present at a concentration of about 0.08 mg / mL to about 0.15 mg / mL.The present invention further provides an embodiment of the above-mentioned pharmaceutical composition, wherein the concentration of the PS80 is about 0.1 mg / mL.

[0018] The present invention provides an embodiment of the aforementioned pharmaceutical composition, wherein the pH of the composition is about 4.6 to about 5.5.The present invention further provides an embodiment of the aforementioned pharmaceutical composition, wherein the pH of the composition is about 4.4 to about 5.2.

[0019] The present invention provides an embodiment of the above-mentioned pharmaceutical composition, wherein the composition comprises about 25 mg / mL enoblituzumab, about 0.18 mg / mL glacial acetic acid, about 0.95 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.7 to about 5.5.

[0020] The present invention provides an embodiment of the pharmaceutical composition described above, wherein the composition comprises about 25 mg / mL enoblituzumab, about 0.27 mg / mL glacial acetic acid, about 0.74 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.6 to about 5.4.

[0021] The present invention provides an embodiment of the above-mentioned pharmaceutical composition, wherein the composition comprises about 120 mg / mL enoblituzumab, about 0.52 mg / mL glacial acetic acid, about 1.5 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.4 to about 5.2.

[0022] The present invention provides embodiments of the above-mentioned pharmaceutical compositions, wherein said composition does not contain an antioxidant.

[0023] The present invention provides an embodiment of the pharmaceutical composition described above, wherein the composition has a shelf life of at least about 18 months at about 2° C. to about 8° C. The present invention further provides an embodiment of the pharmaceutical composition described above, wherein the composition has a shelf life of at least about 24 months at about 2° C. to about 8° C. The present invention further provides an embodiment of the pharmaceutical composition described above, wherein the composition has a shelf life of at least about 36 months at about 2° C. to about 8° C. The present invention further provides an embodiment of the pharmaceutical composition described above, wherein the composition has a shelf life of at least about 48 months at about 2° C. to about 8° C.

[0024] The present invention provides an embodiment of the pharmaceutical composition described above, wherein the osmolality of the composition is about 200 to about 400 mOsm / kg·H2O. The present invention further provides an embodiment of the pharmaceutical composition described above, wherein the osmolality of the composition is about 260 to about 360 mOsm / kg·H2O.

[0025] The invention provides embodiments of the above pharmaceutical compositions, wherein the composition maintains the monomeric purity of the enoblitutuzumab for at least about 3 months at about 25° C. The invention further provides embodiments of the above pharmaceutical compositions, wherein the composition maintains the monomeric purity of the enoblitutuzumab for at least about 18 months at about 2° C. to about 8° C.

[0026] The present invention provides an embodiment of the pharmaceutical composition described above, wherein the composition maintains the heterogeneity profile of the enoblituzumab for at least about 3 months at 25° C. The present invention further provides an embodiment of the pharmaceutical composition described above, wherein the composition maintains the heterogeneity profile of the enoblituzumab for at least about 18 months at about 2° C. to about 8° C.

[0027] The present invention provides an embodiment of the above pharmaceutical composition, wherein the water is sterilized, non-pyrogenic distilled water.

[0028] The present invention provides embodiments of the above pharmaceutical compositions, wherein the composition is sterile.

[0029] The present invention provides a container comprising any of the pharmaceutical compositions disclosed herein, wherein the container comprises about 5 mL, about 10 mL, about 15 mL, about 17 mL, or about 20 mL of the pharmaceutical composition.

[0030] The present invention provides a container comprising the pharmaceutical composition in a volume of about 10 mL, the volume comprising: (a) about 250 mg of enoblituzumab; (b) about 10 mM sodium acetate; (c) about 900 mg of sucrose; (d) about 1 mg of PS80; and (e) water; and the pH of the composition is about 4.6 to about 5.5.

[0031] The present invention provides a container comprising the pharmaceutical composition in a volume of about 10 mL, the volume comprising: (a) about 250 mg of enoblituzumab; (b) about 1.8 mg of glacial acetic acid; (c) about 9.5 mg of sodium acetate trihydrate; (d) about 900 mg of sucrose; (e) about 1 mg of PS80; and (f) water; and the pH of the composition is about 4.7 to about 5.5.

[0032] The present invention provides a container comprising the pharmaceutical composition in a volume of about 10 mL, the volume comprising: (a) about 250 mg of enoblituzumab; (b) about 2.7 mg of glacial acetic acid; (c) about 7.4 mg of sodium acetate trihydrate; (d) about 900 mg of sucrose; (e) about 1 mg of PS80; and (f) water; and the pH of the composition is about 4.6 to about 5.4.

[0033] The present invention provides a container comprising the pharmaceutical composition in a volume of about 10 mL, the volume comprising: (a) about 1,200 mg of enoblituzumab; (b) about 20 mM sodium acetate; (c) about 900 mg of sucrose; (d) about 1 mg of PS80; and (e) water; and the pH of the composition is about 4.4 to about 5.2.

[0034] The present invention provides a container comprising the pharmaceutical composition in a volume of about 10 mL, the volume comprising: (a) about 1,200 mg of enoblituzumab; (b) about 5.2 mg of glacial acetic acid; (c) about 15 mg of sodium acetate trihydrate; (d) about 900 mg of sucrose; (e) about 1 mg of PS80; and (f) water; and the pH of the composition is about 4.4 to about 5.2.

[0035] The present invention provides a container comprising the pharmaceutical composition in a volume of about 17 mL, the volume comprising: (a) about 425 mg of enoblituzumab; (b) about 10 mM; (c) about 1530 mg of sucrose; (d) about 1.7 mg of PS80; and (e) water; and the pH of the composition is about 4.6 to about 5.4.

[0036] The present invention provides a container comprising the pharmaceutical composition in a volume of about 17 mL, the volume comprising: (a) about 425 mg of enoblituzumab; (b) about 3.06 mg of glacial acetic acid; (c) about 16.15 mg of sodium acetate trihydrate; (d) about 1530 mg of sucrose; (e) about 1.7 mg of PS80; and (f) water; and the pH of the composition is about 4.7 to about 5.5.

[0037] The present invention provides a container comprising the pharmaceutical composition in a volume of about 17 mL, the volume comprising: (a) about 425 mg of enoblituzumab; (b) about 4.59 mg of glacial acetic acid; (c) about 12.58 mg of sodium acetate trihydrate; (d) about 1530 mg of sucrose; (e) about 1.7 mg of PS80; and (f) water; and the pH of the composition is about 4.6 to about 5.4.

[0038] The invention further provides a sealed package containing any of the pharmaceutical compositions disclosed herein, or any of the containers disclosed herein.

[0039] The present invention further provides a kit comprising any of the pharmaceutical compositions disclosed herein, any of the containers disclosed herein, or any of the sealed packages disclosed herein, and optionally further comprising instructions for administering the pharmaceutical composition to a subject in need thereof.

[0040] The present invention further provides a sealed package comprising any of the pharmaceutical compositions disclosed herein, any of the containers disclosed herein, or any of the kits disclosed herein, and optionally further comprising instructions for administering the pharmaceutical composition to a subject in need thereof.

[0041] The present invention further provides a method of treating cancer comprising administering enoblituzumab to a subject in need thereof using any of the pharmaceutical compositions disclosed herein, or any of the containers disclosed herein, or any of the sealed packages disclosed herein, or any of the kits disclosed herein.

[0042] The present disclosure further provides a method of treating cancer comprising administering retifanlimab to a subject in need thereof using any of the pharmaceutical compositions disclosed herein, any of the containers disclosed herein, any of the sealed packages disclosed herein, or any of the kits disclosed herein, the method comprising: a) diluting the pharmaceutical composition in a container containing 0.9% sodium chloride or D5W to obtain a dosing solution; b) inverting the container to mix the diluted solution; and c) attaching the container containing the dosing solution to a device for administration to the subject. Includes.

[0043] The invention provides an embodiment of the above method, wherein the container is an IV bag or syringe containing 0.9% sodium chloride.

[0044] The invention provides an embodiment of the above method, wherein the container is an IV bag or a syringe containing D5W.

[0045] The present invention further provides the use of any of the pharmaceutical compositions disclosed herein for the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

[0046] The present invention further provides the use of any of the pharmaceutical compositions disclosed herein, or any of the containers disclosed herein, or any of the sealed packages disclosed herein, or any of the kits disclosed herein, for the treatment of cancer in a subject in need thereof.

[0047] The present invention further provides the use of any of the pharmaceutical compositions disclosed herein, any of the containers disclosed herein, any of the sealed packages disclosed herein, or any of the kits disclosed herein, for the treatment of cancer in a subject in need thereof, said use comprising: a) diluting the pharmaceutical composition in a container containing 0.9% sodium chloride or D5W to obtain a dosing solution; b) inverting the container to mix the diluted solution; and c) attaching the container containing the dosing solution to a device for administration to the subject. Includes.

[0048] The present invention provides an embodiment of the above use, wherein the container is an IV bag or syringe containing 0.9% sodium chloride.

[0049] The present invention provides an embodiment of the above use, wherein the container is an IV bag or a syringe containing D5W.

[0050] The invention provides embodiments of the disclosed methods or uses, wherein the dosing solution maintains the monomeric purity of the enoblitutuzumab at about 25° C. for about 6 hours or at about 2° C. to about 8° C. for about 24 hours.

[0051] The invention provides an embodiment of the disclosed method or use, wherein the administration is by IV infusion over at least about 30 minutes.The invention further provides an embodiment of the disclosed method or use, wherein the administration is by continuous infusion over at least about 60 minutes.The invention further provides an embodiment of the disclosed method or use, wherein the administration is by IV infusion over at least about 120 minutes.

[0052] The present invention provides an embodiment of the disclosed method or use, wherein the pharmaceutical composition is diluted to obtain a body weight based therapeutic dose of about 6 mg / kg to about 15 mg / kg.

[0053] The present invention provides an embodiment of the method or use of the disclosure, wherein the pharmaceutical composition is diluted to obtain a therapeutic dose of about 15 mg / kg body weight.

[0054] The invention provides an embodiment of the disclosed method or use, wherein said administration of said dosing solution is once every three weeks.

[0055] The present invention provides an embodiment of the disclosed method or use, wherein said cancer expresses B7-H3.

[0056] The present invention relates to a method for treating cancer including the treatment of cancers including: adrenal cancer, AIDS-related cancer, alveolar soft part sarcoma, anal cancer, squamous cell carcinoma of the anal canal (SCAC), bladder cancer, bone cancer, brain and spinal cancer, breast cancer, HER2 +Breast cancer, triple-negative breast cancer (TNBC), carotid body tumor, cervical cancer, HPV-associated cervical cancer, chondrosarcoma, chordoma, chromophobe clear cell renal carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, desmoplastic small round cell tumor, ependymoma, endometrial cancer, unselected endometrial cancer, MSI-high endometrial cancer, dMMR endometrial cancer, POLE exonuclease domain mutation-positive endometrial cancer, Ewing's sarcoma, extraskeletal myxoid chondrosarcoma, gallbladder cancer, bile duct cancer, cholangiocarcinoma, gastric cancer cancer), esophagogastric junction (GEJ) cancer, gestational trophoblastic disease, germ cell tumors, glioblastoma, head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), hematological malignancies, hepatocellular carcinoma, islet cell tumors, Kaposi's sarcoma, kidney cancer, leukemia, acute myeloid leukemia, liposarcoma / malignant lipomatous tumors, liver cancer, hepatocellular carcinoma (HCC), lymphoma, diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), medulloblastoma, melanoma, uveal

[0023] An embodiment of the method or use of the present disclosure is provided, wherein the cancer is selected from the group consisting of melanoma, meningioma, Merkel cell carcinoma, mesothelioma, mesothelial pharyngeal carcinoma, multiple endocrine neoplasia, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumor, ovarian cancer, pancreatic cancer, papillary thyroid cancer, parathyroid tumor, pediatric cancer, peripheral nerve sheath tumor, pharyngeal cancer, pheochromocytoma, pituitary tumor, prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), posterior uveal melanoma, renal metastatic cancer, rhabdoid tumor, rhabdomyosarcoma, sarcoma, skin cancer, small round blue cell tumor of childhood, neuroblastoma, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, synovial sarcoma, testicular cancer, thymic carcinoma, thymoma, thyroid cancer, urothelial carcinoma, and uterine cancer.

[0057] The present invention provides an embodiment of the method or use of the disclosure, wherein the cancer is anal cancer, bladder cancer, breast cancer, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, GEJ cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, prostate cancer, skin cancer, and urothelial cancer.

[0058] The present invention provides an embodiment of the disclosed method or use, wherein the anal cancer is SCAC, the lung cancer is NSCLC, the breast cancer is TNBC, the skin cancer is melanoma or Merkel cell carcinoma, the head and neck cancer is SCCHN, and the prostate cancer is mCRPC.The present invention provides an embodiment of the disclosed method or use, wherein the subject is a human subject. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] The present invention provides pharmaceutical compositions comprising an anti-human B7-H3 ("hB7-H3") antibody ("enoblituzumab") and a buffer for storage and administration. The present invention further provides containers and kits comprising the pharmaceutical compositions. The present invention further provides uses of the pharmaceutical compositions, containers, and kits containing enoblituzumab, e.g., for treating cancer with a therapeutically or prophylactically effective amount of enoblituzumab, and in certain embodiments, for treating cancers that express B7-H3.

[0060] I. Enoblituzumab Enobrituzumab (also known as enobrituzumab; CAS Registry Number 1353485-38-7, see, e.g., U.S. Patent No. 8,802,093) is an Fc-optimized monoclonal antibody that binds to B7-H3 and mediates enhanced ADCC activity. Enobrituzumab contains a human IgG1 Fc region containing L235V, F243L, R292P, Y300L, and P396L substitutions to enhance ADCC activity, where the numbering of residues in the IgG heavy chain is as follows: Kabat et al., Sequences of Proteins of Immunological Interest, 5 th This is the EU index numbering in the Ed. Public Health Service, NH1, MD (1991) and refers to the numbering of human IgG1 EU antibodies. The amino acid sequences of the heavy and light chains of enoblituzumab are provided below (WHO Drug Information 2016, Recommended INN: List 76, 30(3)):496). The CDRs as defined by Kabat are underlined.

[0061] The amino acid sequence of the heavy chain of enoblitzumab is (SEQ ID NO: 1) (CDR H Residues are shown in bold and underlined, constant regions are shown double underlined, Fc region substitutions are shown in bold and double underlined): JPEG2024526773000001.jpg51155

[0062] The amino acid sequence of the light chain of enoblitzumab is (SEQ ID NO:2) (CDR L Residues are shown in bold and underlined, and constant regions are shown double underlined): JPEG2024526773000002.jpg28145

[0063] II. Pharmaceutical Compositions The pharmaceutical compositions of the invention comprise enoblitutuzumab, a buffer, and a stabilizer, and are also referred to herein as "enoblitutuzumab compositions" or "enoblitutuzumab drug product (DP) compositions."

[0064] As used herein, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which the phrase is used. If there are uses of the phrase that are not clear to a person of ordinary skill in the art and not otherwise defined herein, "about" will mean up to plus or minus 10% of the particular term, given the context in which the phrase is used.

[0065] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a" component includes aspects having two or more of such components unless the context clearly dictates otherwise. Also, when the word "or" is used without the preceding "either" (or similar language indicating that "or" is clearly exclusive, such as "only one of x or y"), the word is intended to be interpreted as inclusive (e.g., "x or y" means one or both of x or y).

[0066] The term "and / or" is also to be construed as inclusive (e.g., "x and / or y" means one or both of x and y). When "and / or" or "or" is used as a conjunction with a group of more than two items, the group is to be construed as including only one item, all items, or any combination or number of items. Furthermore, as used in the specification and claims, the terms "have," "including," and "include" are to be construed as equivalent to the term "comprise." There may optionally be elements other than the elements specifically identified by the "and / or" clause, related or unrelated to the elements specifically identified above. As a non-limiting example, a reference to "X and / or Y" can refer in some embodiments to only X (optionally including elements other than Y); in some embodiments to only Y (optionally including elements other than X); and in some further embodiments to both X and Y (optionally including other elements).

[0067] As used herein, "acetate" refers to the acetate component of a pharmaceutical composition. For example, the acetate component can be composed of acetic acid, an acetate salt, and / or an acetate buffer.

[0068] As used herein, the term "aqueous" refers to a solution that contains water.

[0069] As used herein, the term "stable" refers to enoblituzumab substantially retaining its physical stability, chemical stability, pharmaceutical activity, and / or its biological activity upon storage.

[0070] The term "shelf-life" refers to the period over which a pharmaceutical composition can be stored while substantially retaining its physical stability, chemical stability, pharmaceutical activity, and / or biological activity.

[0071] As will be understood by those skilled in the art, for all purposes, particularly in terms of providing a written description, all ranges disclosed herein include all possible subranges and combinations of subranges thereof, including the endpoints. Thus, all ranges disclosed are to be understood to include and provide support for the claims set forth herein, any subranges or individual values ​​subsumed by each range. For example, if a range of 1 to 10 is described, this is to be understood to include and provide support for the claims set forth herein, any subranges or individual values ​​between and including the minimum value of 1 and the maximum value of 10; i.e., any subrange beginning with a minimum value of 1 or more and ending with a maximum value of 10 or less (e.g., 5.5 to 10, 2.34 to 3.56, etc.), or any value between 1 and 10 (e.g., 3, 5.8, 9.9994, etc.).

[0072] Any range recited is readily recognizable as fully descriptive and allowing the range to be equally divided into at least 2, 3, 4, 5, 10, etc. As a non-limiting example, each range discussed herein can be readily divided into a lower third, a middle third, an upper third, etc. As will also be appreciated by those skilled in the art, all expressions such as "up to," "at least," "greater than," "less than" and the like refer to ranges that are inclusive of the recited numbers and that can be subsequently divided into subranges as discussed herein. Additionally, as will be appreciated by those skilled in the art, a range includes individual numbers. Thus, for example, a group having 1-3 layers refers to a group having 1, 2, or 3 layers. Similarly, a group having 1-5 layers refers to a group having 1, 2, 3, 4, or 5 layers.

[0073] The embodiments disclosed herein as exemplary may suitably be practiced in the absence of any element or elements, or any limitation, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., are to be understood in an open and non-limiting sense. Furthermore, the terms and expressions employed herein are used as terms of description, not of limitation, and the use of these terms and expressions is not intended to exclude any equivalents or portions of the features shown and described, recognizing that various modifications are possible within the scope of the claimed technology. Furthermore, the phrase "consisting essentially of" is to be understood as including the elements specifically described and additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any elements not specified.

[0074] Definitions contained in texts incorporated by reference are excluded to the extent that they conflict with definitions in this disclosure.

[0075] The present disclosure provides pharmaceutical compositions that substantially retain the physical and chemical stability of enoblituzumab, as well as its pharmaceutical and / or biological activity, upon storage. In one embodiment, about 90% or more, about 80% or more, about 70% or more, or about 60% or more of the physical stability, chemical stability, pharmaceutical activity and / or biological activity of enoblituzumab is retained during storage of the pharmaceutical composition of the present disclosure. In one embodiment, about 90% or more, about 85% or more, about 80% or more, about 75% or more, about 70% or more, about 65% or more, or about 60% or more of the physical stability, chemical stability, pharmaceutical activity and / or biological activity of enoblituzumab is retained during the shelf life. The shelf life of a pharmaceutical composition is generally selected based on the period during which the molecule is stable in the composition.

[0076] In one embodiment, the shelf life of the pharmaceutical composition of the present invention is at least about 1 month at about 25°C, at least about 2 months at about 25°C, at least about 3 months at about 25°C, at least about 4 months at about 25°C, at least about 6 months at about 25°C, at least about 6 months at 2-8°C, at least about 12 months at 2-8°C, at least about 18 months at 2-8°C, at least about 24 months at 2-8°C, at least about 30 months at 2-8°C, at least about 36 months at 2-8°C, at least about 48 months at 2-8°C, or more than about 48 months at 2-8°C. In another embodiment, the shelf life of the pharmaceutical composition of the present invention is at least about 6 months at about 25°C. In another embodiment, the shelf life of the pharmaceutical composition of the present invention is at least about 24 months at 2-8°C. In another embodiment, the shelf life of the pharmaceutical composition of the present invention is at least about 36 months at 2-8°C. In another embodiment, the shelf life of the pharmaceutical composition of the present invention is at least about 48 months at 2-8°C.

[0077] One measure of physical and chemical stability is the monomeric purity of enoblitutuzumab in the pharmaceutical composition of the present invention or in the dosage solution of the present invention. The monomeric purity of enoblitutuzumab can be determined by assessing the amount of protein having the expected molecular weight (monomeric enoblitutuzumab), species having a molecular weight higher than the monomer (HMW species), and / or species having a molecular weight lower than the monomer (LMW species) in such a composition or solution by any suitable method. Thus, the loss of monomeric purity can be measured by determining the loss of protein having the expected molecular weight (monomeric enoblitutuzumab) and / or the accumulation of HMW and / or LMW species after a designated period of time. In certain embodiments, the percentage (%) of each species (monomeric, HMW, and LMW) is calculated as a percentage (%) of the total protein. In one embodiment, the loss of monomeric purity of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention is about 15% or less, or about 10% or less, or about 5% or less, or about 4% or less, or about 3% or less, or about 2% or less, or about 1% or less over a designated period of time. In one embodiment, the loss of monomeric purity of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention is about 6% or less over a designated period of time. In one embodiment, the loss of monomeric purity of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention is about 5% or less over a designated period of time. In another embodiment, the loss of monomeric purity of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention is less than about 4% over a designated period of time. In another embodiment, the loss of monomeric purity of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention is about 3% or less over a designated period of time. In another embodiment, the loss of monomeric purity of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention is about 2% or less over the indicated time period. In certain embodiments, the HMW and / or LMW species of enoblituzumab in a composition of the invention or in a dosing solution of the invention are measured by size exclusion high performance liquid chromatography (SE-HPLC).In one such embodiment, the percentages of each species are calculated as the area of ​​the SE-HPLC species peaks (i.e., monomeric, HMW, LMW) divided by the sum of all peaks, i.e., the percentage of total protein.

[0078] In other embodiments, the monomeric purity of enoblituzumab in the pharmaceutical composition of the invention is maintained for at least about 1 month at about 25° C., at least about 2 months at about 25° C., at least about 3 months at about 25° C., at least about 4 months at about 25° C., at least about 6 months at about 25° C., at least about 6 months at about 2° C. to about 8° C., at least about 12 months at about 2° C. to about 8° C., at least about 18 months at about 2° C. to about 8° C., at least about 24 months at about 2° C. to about 8° C., at least about 30 months at about 2° C. to about 8° C., at least about 36 months at about 2° C. to about 8° C., at least about 48 months, or more than about 48 months at about 2° C. to about 8° C. In one embodiment, the monomeric purity of enoblituzumab in the pharmaceutical composition of the invention is maintained for at least about 6 months at about 25° C. In another embodiment, the monomeric purity of enoblitutuzumab in the pharmaceutical composition of the invention is maintained for about 36 months or more at about 2° C. to about 8° C. In another embodiment, the monomeric purity of enoblitutuzumab in the pharmaceutical composition of the invention is maintained for about 48 months at about 2° C. to about 8° C.

[0079] Another measure of stability is the stability of the charge heterogeneity profile of enobrituzumab in the pharmaceutical composition of the present invention or in the dosage solution of the present invention. The protein composition may contain various variants with different isoelectric points (pI). Such variants are called charge variants. Thus, the heterogeneity profile can be determined by measuring the main charge peak (MCP), acidic variant (AV), and basic variant (BV) by any suitable method. For example, the enobrituzumab composition of the present invention can contain MCP, AV, and BV components, and the change in the heterogeneity profile can be measured by determining the loss of MCP and / or the accumulation of AV and / or BV after the indicated time. In one embodiment, the MCP of enoblitutuzumab in the pharmaceutical composition of the invention or in the dosing solution of the invention decreases by about 15% or less, or about 10% or less, or about 5% or less, or about 4% or less, or about 3% or less, or about 2% or less, or about 1% or less over the indicated time period. In one embodiment, the AV of enoblitutuzumab in the pharmaceutical composition of the invention or in the dosing solution of the invention increases by about 15% or less, or about 10% or less, or about 5% or less, or about 4% or less, or about 3% or less, or about 2% or less, or about 1% or less over the indicated time period. In another embodiment, the BV of enoblitutuzumab in the pharmaceutical composition of the invention or in the dosing solution of the invention increases by about 15% or less, or about 10% or less, or about 5% or less, or about 4% or less, or about 3% or less, or about 2% or less, or about 1% or less over the indicated time period. In another embodiment, the MCP of enoblitutuzumab in the pharmaceutical composition of the invention or in the dosing solution of the invention is reduced by about 7% or less over the indicated time period. In another embodiment, the MCP of enoblitutuzumab in the pharmaceutical composition of the invention or in the dosing solution of the invention is reduced by about 6% or less over the indicated time period. In another embodiment, the MCP of enoblitutuzumab in the pharmaceutical composition of the invention or in the dosing solution of the invention is reduced by about 5% or less over the indicated time period.In another embodiment, the AV of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention increases by about 7% or less over the indicated time period. In another embodiment, the AV of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention increases by about 6% or less over the indicated time period. In another embodiment, the AV of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention increases by about 5% or less over the indicated time period. In another embodiment, the BV of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention increases by about 4% or less over the indicated time period. In another embodiment, the BV of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention increases by about 3% or less over the indicated time period. In another embodiment, the BV of enoblituzumab in a pharmaceutical composition of the invention or in a dosing solution of the invention increases by about 2% or less over the indicated time period. In certain embodiments, the MCP, AV, and BV of enoblituzumab in the pharmaceutical composition of the invention or the dosing solution of the invention are measured by ion exchange high performance liquid chromatography (IE-HPLC). In certain embodiments, the MCP, AV, and BV of enoblituzumab in the pharmaceutical composition of the invention or the dosing solution of the invention are measured by capillary isoelectric focusing (cIEF).

[0080] In other embodiments, the heterogeneity profile of enoblitutuzumab in the pharmaceutical composition of the invention is maintained for at least about 1 month at about 25° C., at least about 2 months at about 25° C., at least about 3 months at about 25° C., at least about 4 months at about 25° C., at least about 6 months at about 25° C., at least about 6 months at about 2° C. to about 8° C., at least about 12 months at about 2° C. to about 8° C., at least about 18 months at about 2° C. to about 8° C., at least about 24 months at about 2° C. to about 8° C., at least about 30 months at about 2° C. to about 8° C., at least about 36 months at about 2° C. to about 8° C., at least about 48 months, or more than about 48 months at about 2° C. to about 8° C. In one embodiment, the heterogeneity profile of enoblitutuzumab in the pharmaceutical composition of the invention is maintained for at least about 6 months at about 25° C. In another embodiment, the heterogeneity profile of enoblitutuzumab in the pharmaceutical composition of the invention is maintained for about 36 months or more at about 2° C. to about 8° C. In another embodiment, the heterogeneity profile of enoblitutuzumab in the pharmaceutical composition of the invention is maintained for about 48 months at about 2° C. to about 8° C.

[0081] A. Enoblituzumab Compositions The components of the pharmaceutical compositions of the invention (i.e., enoblitutuzumab compositions) can be supplied mixed in unit dosage form, e.g., as a liquid composition in an airtight container such as a vial, ampoule, or sachet indicating the quantity of active agent. In one embodiment, the pharmaceutical compositions of the invention are supplied as a liquid solution. Such liquid solutions can be stored in their original container at about 2° C. to about 8° C. until ready for administration, although such liquid solutions can also be stored at room temperature (about 25° C.) for short periods of time prior to administration.

[0082] In certain embodiments in which the enoblitutuzumab compositions of the invention are administered by injection, the compositions can be dispensed, for example, using a syringe, container, bag, or infusion bottle containing sterile 0.9% sodium chloride (e.g., saline). In certain embodiments in which the enoblitutuzumab compositions of the invention are administered by injection, 0.9% sodium chloride can be provided so that the ingredients can be mixed prior to administration, as detailed herein. Such enoblitutuzumab compositions can include a prophylactically or therapeutically effective amount of enoblitutuzumab.

[0083] In certain embodiments in which the enoblitutuzumab compositions of the invention are administered by injection, the compositions can be dispensed using, for example, a syringe, container, bag, or infusion bottle containing 5% dextrose in sterile water ("D5W"). In certain embodiments in which the enoblitutuzumab compositions of the present disclosure are administered by injection, D5W can be provided to allow the ingredients to mix prior to administration as detailed herein. Such enoblitutuzumab compositions can include a prophylactically or therapeutically effective amount of enoblitutuzumab.

[0084] In one embodiment, a pharmaceutical composition of the invention comprises enoblitutuzumab, acetate, sucrose, PS80, and water. In certain embodiments, a pharmaceutical composition of the invention does not comprise an antioxidant (e.g., methionine).

[0085] The acetate component can be comprised of acetic acid and acetate salts. Acceptable acetate salts include, but are not limited to: calcium acetate, magnesium acetate, potassium acetate, sodium acetate, and zinc acetate. In one embodiment, the acetate salts include glacial acetic acid and sodium acetate.

[0086] In one embodiment, the pharmaceutical composition of the present invention comprises enoblituzumab at a concentration of about 5 mg / mL to about 200 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enoblituzumab at a concentration of about 5 mg / mL to about 60 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enoblituzumab at a concentration of about 20 mg / mL to about 130 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enoblituzumab at a concentration of about 20 mg / mL to about 40 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enoblituzumab at a concentration of about 20 mg / mL to about 30 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enoblituzumab at a concentration of about 22.5 mg / mL to about 27.5 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enoblituzumab at a concentration of about 60 mg / mL to about 130 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enobrituzumab at a concentration of about 85 mg / mL to about 105 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enobrituzumab at a concentration of about 115 mg / mL to about 125 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enobrituzumab at a concentration of about 135 mg / mL to about 155 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enobrituzumab at a concentration of about 165 mg / mL to about 175 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enobrituzumab at a concentration of about 185 mg / mL to about 200 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enobrituzumab at a concentration of about 25 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enobrituzumab at a concentration of about 60 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises enobrituzumab at a concentration of about 90 mg / mL. In another embodiment, the pharmaceutical composition of the invention comprises enoblituzumab at a concentration of about 120 mg / mL. Enoblituzumab concentrations between any of these values ​​are also contemplated, e.g., about 10 mg / mL, about 22 mg / mL, about 27 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 80 mg / mL, about 100 mg / mL, about 150 mg / mL, etc.

[0087] In one embodiment, the pharmaceutical composition of the present invention comprises about 5 mM to about 30 mM acetate. In another embodiment, the pharmaceutical composition of the present invention comprises about 5 mM to about 25 mM acetate. In another embodiment, the pharmaceutical composition of the present invention comprises about 8 mM to about 24 mM acetate. In another embodiment, the pharmaceutical composition of the present invention comprises about 7.5 mM to about 15 mM acetate. In another embodiment, the pharmaceutical composition of the present invention comprises about 8 mM to about 12 mM acetate. In another embodiment, the pharmaceutical composition of the present invention comprises about 9 mM to about 11 mM acetate. In one embodiment, the pharmaceutical composition of the present invention comprises about 16 mM to about 24 mM acetate. In one embodiment, the pharmaceutical composition of the present invention comprises about 18 mM to about 22 mM acetate. In another embodiment, the pharmaceutical composition of the present invention comprises about 10 mM acetate. In another embodiment, the pharmaceutical composition of the present invention comprises about 20 mM acetate. Acetate concentrations between any of these values ​​are also contemplated, e.g., about 8 mM, about 14 mM, about 18 mM, etc. In one embodiment, the acetate in the composition of the present invention comprises glacial acetic acid and sodium acetate (e.g., anhydrous sodium acetate, sodium acetate monohydrate, and / or sodium acetate trihydrate). It is understood that the desired acetate concentration can be obtained by using sodium acetate monohydrate and / or anhydrous sodium acetate and / or sodium acetate trihydrate in combination with glacial acetic acid. As provided herein, other forms of acetate, including but not limited to magnesium acetate, potassium acetate, calcium acetate, and zinc acetate, can be used in place of sodium acetate in the acetate buffer.

[0088] In one embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.05 mg / mL to about 0.8 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.1 mg / mL to about 0.65 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.1 mg / mL to about 0.35 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.16 mg / mL to about 0.20 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.23 mg / mL to about 0.30 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.4 mg / mL to about 0.65 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.45 mg / mL to about 0.57 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.18 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.27 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.52 mg / mL. Glacial acetic acid concentrations between any of these values ​​are also contemplated, e.g., about 0.08 mg / mL, 0.15 mg / mL, 0.25 mg / mL, etc.

[0089] In one embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 0.50 mg / mL to about 2.0 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 0.6 mg / mL to about 1.8 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 0.6 mg / mL to about 1.2 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 0.86 mg / mL to about 1.1 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 0.66 mg / mL to about 0.81 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 1.2 mg / mL to about 1.8 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 1.35 mg / mL to about 1.65 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 0.74 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 0.95 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sodium acetate trihydrate at a concentration of about 1.5 mg / mL. Sodium acetate trihydrate concentrations between any of these values ​​are also contemplated, e.g., about 0.9 mg / mL, about 1.2 mg / mL, about 1.7 mg / mL, etc.

[0090] In one embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.05 mg / mL to about 0.8 mg / mL and sodium acetate trihydrate at a concentration of about 0.50 mg / mL to about 2.0 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.1 mg / mL to about 0.65 mg / mL and sodium acetate trihydrate at a concentration of about 0.6 mg / mL to about 1.8 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.1 mg / mL to about 0.35 mg / mL and sodium acetate trihydrate at a concentration of about 0.6 mg / mL to about 1.2 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.16 mg / mL to about 0.20 mg / mL and sodium acetate trihydrate at a concentration of about 0.86 mg / mL to about 1.1 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.23 mg / mL to about 0.30 mg / mL and sodium acetate trihydrate at a concentration of about 0.66 mg / mL to about 0.81 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.4 mg / mL to about 0.65 mg / mL and sodium acetate trihydrate at a concentration of about 1.2 mg / mL to about 1.8 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.45 mg / mL to about 0.57 mg / mL and sodium acetate trihydrate at a concentration of about 1.35 mg / mL to about 1.65 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid at a concentration of about 0.27 mg / mL and sodium acetate trihydrate at a concentration of about 0.74 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid in the concentration of about 0.18 mg / mL and sodium acetate trihydrate in the concentration of about 0.95 mg / mL.In another embodiment, the pharmaceutical composition of the present invention comprises glacial acetic acid in the concentration of about 0.52 mg / mL and sodium acetate trihydrate in the concentration of about 1.5 mg / mL.

[0091] In one embodiment, the pharmaceutical composition of the present invention comprises sucrose at a concentration of about 50 mg / mL to about 130 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sucrose at a concentration of about 72 mg / mL to about 108 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sucrose at a concentration of about 76 mg / mL to about 104 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sucrose at a concentration of about 80 mg / mL to about 100 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises sucrose at a concentration of about 90 mg / mL. Sucrose concentrations between any of these values ​​are also contemplated, e.g., about 85 mg / mL, about 87 mg / mL, about 92 mg / mL, etc.

[0092] In one embodiment, the pharmaceutical composition of the present invention comprises PS80 at a concentration of about 0.05 mg / mL to about 0.6 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises PS80 at a concentration of about 0.08 mg / mL to about 0.53 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises PS80 at a concentration of about 0.08 mg / mL to about 0.2 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises PS80 at a concentration of about 0.08 mg / mL to about 0.12 mg / mL. In another embodiment, the pharmaceutical composition of the present invention comprises PS80 at a concentration of about 0.1 mg / mL. PS80 concentrations between any of these values ​​are also contemplated, e.g., about 0.09 mg / mL, about 0.11 mg / mL, about 0.13 mg / mL, etc.

[0093] In one embodiment, the pH of the pharmaceutical composition of the present invention is about 4.0 to about 6.0. In another embodiment, the pH of the pharmaceutical composition of the present invention is about 4.4 to about 5.6. In another embodiment, the pH of the pharmaceutical composition of the present invention is about 4.3 to about 5.3. In another embodiment, the pH of the pharmaceutical composition of the present invention is about 4.5 to about 5.5. In another embodiment, the pH of the pharmaceutical composition of the present invention is about 4.7 to about 5.5 (i.e., about 5.1±0.4). In another embodiment, the pH of the pharmaceutical composition of the present invention is about 4.6 to about 5.4 (i.e., about 5.0±0.4). In another embodiment, the pH of the pharmaceutical composition of the present invention is about 4.4 to about 5.2 (i.e., about 4.8±0.4). In another embodiment, the pH of the pharmaceutical composition of the present invention is about 4.8. In another embodiment, the pH of the pharmaceutical composition of the present invention is about 5.0. In another embodiment, the pH of the pharmaceutical composition of the present invention is about 5.1. pH values ​​between any of these values ​​are also contemplated, such as a pH of about 4.7, a pH of about 4.9, a pH of about 5.3, or a pH of about 5.5.

[0094] In one embodiment, the pharmaceutical composition of the present invention comprises about 5 mg / mL to about 200 mg / mL of enobrituzumab, about 5 mM to about 30 mM of sodium acetate, about 50 mg / mL to about 130 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.0 to about 6.0. In another embodiment, the pharmaceutical composition of the present invention comprises about 5 mg / mL to about 200 mg / mL of enobrituzumab, about 8 mM to about 24 mM of sodium acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.6.

[0095] In one embodiment, the pharmaceutical composition of the present invention comprises about 20 mg / mL to about 40 mg / mL of enobrituzumab, about 7.5 mM to about 15 mM of sodium acetate, about 50 mg / mL to about 130 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.0 to about 6.0. In another embodiment, the pharmaceutical composition of the present invention comprises about 20 mg / mL to about 40 mg / mL of enobrituzumab, about 8 mM to about 12 mM of sodium acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.08 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.5 to about 5.5. In another embodiment, the pharmaceutical composition of the present invention comprises about 20 mg / mL to about 30 mg / mL of enobrituzumab, about 9 mM to about 11 mM of sodium acetate, about 76 mg / mL to about 104 mg / mL of sucrose, about 0.08 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.5 to about 5.5. In another embodiment, the pharmaceutical composition of the present invention comprises about 25 mg / mL of enobrituzumab, about 10 mM of sodium acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.6 to about 5.5. In another embodiment, the pharmaceutical composition of the present invention comprises about 25 mg / mL of enobrituzumab, about 10 mM of sodium acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 5.1. In another embodiment, a pharmaceutical composition comprises about 25 mg / mL enoblituzumab, about 10 mM sodium acetate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, wherein the pH of the composition is about 5.0.

[0096] In another embodiment, the pharmaceutical composition of the present invention comprises about 60 mg / mL to about 200 mg / mL of enobrituzumab, about 16 mM to about 24 mM of sodium acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.3 to about 5.3. In another embodiment, the pharmaceutical composition of the present invention comprises about 60 mg / mL to about 200 mg / mL of enobrituzumab, about 18 mM to about 22 mM of sodium acetate, about 76 mg / mL to about 104 mg / mL of sucrose, about 0.08 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, the pharmaceutical composition of the present invention comprises about 90 mg / mL to about 200 mg / mL of enoblituzumab, about 20 mM sodium acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, the pharmaceutical composition of the present invention comprises about 120 mg / mL of enoblituzumab, about 20 mM sodium acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, the pharmaceutical composition of the present invention comprises about 120 mg / mL of enoblituzumab, about 20 mM sodium acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.8.

[0097] In one embodiment, the pharmaceutical composition of the present invention comprises about 5 mg / mL to about 200 mg / mL of enoblituzumab, about 0.05 mg / mL to about 0.8 mg / mL of glacial acetic acid, about 0.5 mg / mL to about 2.0 mg / mL of sodium acetate trihydrate, about 50 mg / mL to about 130 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, wherein the pH of the composition is about 4.0 to about 6.0. In another embodiment, a pharmaceutical composition of the present invention comprises about 5 mg / mL to about 200 mg / mL of enoblituzumab, about 0.1 mg / mL to about 0.65 mg / mL of glacial acetic acid, about 0.6 mg / mL to about 1.8 mg / mL of sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, wherein the pH of the composition is about 4.4 to about 5.6.

[0098] In one embodiment, a pharmaceutical composition of the invention comprises about 20 mg / mL to about 30 mg / mL of enoblituzumab, about 0.1 mg / mL to about 0.35 mg / mL of glacial acetic acid, about 0.6 mg / mL to about 1.2 mg / mL of sodium acetate trihydrate, 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, wherein the pH of the composition is about 4.5 to about 5.5. In one embodiment, the pharmaceutical composition of the present invention comprises about 22.5 mg / mL to about 27.5 mg / mL of enobrituzumab, about 0.1 mg / mL to about 0.35 mg / mL of glacial acetic acid, about 0.6 mg / mL to about 1.2 mg / mL of sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.5 to about 5.5. In one embodiment, the pharmaceutical composition of the present invention comprises about 25 mg / mL of enobrituzumab, about 0.18 mg / mL of glacial acetic acid, about 0.95 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.7 to about 5.5. In another embodiment, the pharmaceutical composition of the present invention comprises about 25 mg / mL enobrituzumab, about 0.18 mg / mL glacial acetic acid, about 0.95 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 5.1. In one embodiment, the pharmaceutical composition of the present invention comprises about 25 mg / mL enobrituzumab, about 0.27 mg / mL glacial acetic acid, about 0.74 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.6 to about 5.4. In another embodiment, a pharmaceutical composition comprises about 25 mg / mL enoblituzumab, about 0.27 mg / mL glacial acetic acid, about 0.74 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, wherein the pH of the composition is about 5.0.

[0099] In one embodiment, a pharmaceutical composition of the invention comprises about 60 mg / mL to about 200 mg / mL of enoblituzumab, about 0.4 mg / mL to about 0.65 mg / mL of glacial acetic acid, about 1.2 mg / mL to about 1.8 mg / mL of sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, wherein the pH of the composition is about 4.3 to about 5.3. In another embodiment, the pharmaceutical composition of the present invention comprises about 90 mg / mL to about 200 mg / mL of enobrituzumab, about 0.4 mg / mL to about 0.65 mg / mL of glacial acetic acid, about 1.2 mg / mL to about 1.8 mg / mL of sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.3 to about 5.3. In another embodiment, the pharmaceutical composition of the present invention comprises about 120 mg / mL of enobrituzumab, about 0.52 mg / mL of glacial acetic acid, about 1.5 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, a pharmaceutical composition comprises about 120 mg / mL enoblituzumab, about 0.52 mg / mL glacial acetic acid, about 1.5 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, wherein the pH of the composition is about 4.8.

[0100] In one embodiment, about 5 mL to about 20 mL of the pharmaceutical composition of the present invention can contain about 25 mg / mL of enobrituzumab, about 0.18 mg / mL of glacial acetic acid, about 0.95 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.7 to about 5.5. In another embodiment, about 5 mL to about 20 mL of the pharmaceutical composition of the present invention can contain about 25 mg / mL of enobrituzumab, about 0.18 mg / mL of glacial acetic acid, about 0.95 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 5.1.

[0101] In another embodiment, about 5 mL to about 20 mL of the pharmaceutical composition of the present invention can contain about 25 mg / mL of enobrituzumab, about 0.27 mg / mL of glacial acetic acid, about 0.74 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.6 to about 5.4. In another embodiment, about 5 mL to about 20 mL of the pharmaceutical composition of the present invention can contain about 25 mg / mL of enobrituzumab, about 0.27 mg / mL of glacial acetic acid, about 0.74 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 5.0.

[0102] In one embodiment, about 5 mL to about 20 mL of the pharmaceutical composition of the present invention can contain about 120 mg / mL enobrituzumab, about 20 mM sodium acetate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, about 5 mL to about 20 mL of the pharmaceutical composition of the present invention can contain about 120 mg / mL enobrituzumab, about 20 mM sodium acetate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.8.

[0103] In another embodiment, about 5 mL to about 20 mL of the pharmaceutical composition of the present invention can contain about 120 mg / mL of enobrituzumab, about 0.52 mg / mL of glacial acetic acid, about 1.5 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, about 5 mL to about 20 mL of the pharmaceutical composition of the present invention can contain about 120 mg / mL of enobrituzumab, about 0.52 mg / mL of glacial acetic acid, about 1.5 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.8.

[0104] In one embodiment, about 5 mL of the pharmaceutical composition of the present invention comprises about 125 mg of enobrituzumab, about 10 mM sodium acetate, about 450 mg of sucrose, about 0.5 mg of PS80, and water, and the pH of the composition is about 4.6 to about 5.5. In another embodiment, about 5 mL of the pharmaceutical composition of the present invention comprises about 125 mg of enobrituzumab, about 10 mM sodium acetate, about 450 mg of sucrose, about 0.5 mg of PS80, and water, and the pH of the composition is about 5.1. In another embodiment, about 5 mL of the pharmaceutical composition of the present invention comprises about 125 mg of enobrituzumab, about 10 mM sodium acetate, about 450 mg of sucrose, about 0.5 mg of PS80, and water, and the pH of the composition is about 5.0.

[0105] In one embodiment, about 5 mL of the pharmaceutical composition of the present invention comprises about 125 mg of enoblituzumab, about 0.9 mg of glacial acetic acid, about 4.75 mg of sodium acetate trihydrate, about 450 mg of sucrose, about 0.5 mg of PS80, and water, and the pH of the composition is about 4.7 to about 5.5. In another embodiment, about 5 mL of the pharmaceutical composition of the present invention comprises about 125 mg of enoblituzumab, about 0.9 mg of glacial acetic acid, about 4.75 mg of sodium acetate trihydrate, about 450 mg of sucrose, about 0.5 mg of PS80, and water, and the pH of the composition is about 5.1. In another embodiment, about 5 mL of the pharmaceutical composition of the present invention comprises about 125 mg of enoblituzumab, about 0.9 mg of glacial acetic acid, about 4.75 mg of sodium acetate trihydrate, about 450 mg of sucrose, about 0.5 mg of PS80, and water, and the pH of the composition is about 4.6 to about 5.4. In one embodiment, about 5 mL of the pharmaceutical composition of the present invention comprises about 125 mg of enoblituzumab, about 1.35 mg of glacial acetic acid, about 3.7 mg of sodium acetate trihydrate, about 450 mg of sucrose, about 0.5 mg of PS80, and water, and the pH of the composition is about 4.8.

[0106] In one embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 250 mg of enobrituzumab, about 10 mM sodium acetate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 4.6 to about 5.5. In another embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 250 mg of enobrituzumab, about 10 mM sodium acetate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 5.1. In another embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 250 mg of enobrituzumab, about 10 mM sodium acetate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 5.0.

[0107] In one embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 250 mg of enoblituzumab, about 1.8 mg of glacial acetic acid, about 9.5 mg of sodium acetate trihydrate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 4.7 to about 5.5. In another embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 250 mg of enoblituzumab, about 1.8 mg of glacial acetic acid, about 9.5 mg of sodium acetate trihydrate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 5.1. In another embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 250 mg of enoblituzumab, about 1.8 mg of glacial acetic acid, about 9.5 mg of sodium acetate trihydrate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 4.6 to about 5.4. In one embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 250 mg of enoblituzumab, about 2.7 mg of glacial acetic acid, about 7.4 mg of sodium acetate trihydrate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 4.8.

[0108] In an alternative embodiment, about 17 mL of the pharmaceutical composition of the present invention comprises about 425 mg of enobrituzumab, about 10 mM sodium acetate trihydrate, about 1530 mg of sucrose, about 1.7 mg of PS80, and water, and the pH of the composition is about 4.6 to about 5.5. In another alternative embodiment, about 17 mL of the pharmaceutical composition of the present invention comprises about 425 mg of enobrituzumab, about 10 mM sodium acetate trihydrate, about 1530 mg of sucrose, about 1.7 mg of PS80, and water, and the pH of the composition is about 5.1. In another alternative embodiment, about 17 mL of the pharmaceutical composition of the present invention comprises about 425 mg of enobrituzumab, about 10 mM sodium acetate trihydrate, about 1530 mg of sucrose, about 1.7 mg of PS80, and water, and the pH of the composition is about 5.0.

[0109] In another alternative embodiment, about 17 mL of the pharmaceutical composition of the present invention comprises about 425 mg of enobritusumab, about 3.06 mg of glacial acetic acid, about 16.15 mg of sodium acetate trihydrate, about 1530 mg of sucrose, about 1.7 mg of PS80, and water, and the pH of the composition is about 4.7 to about 5.5. In another alternative embodiment, about 17 mL of the pharmaceutical composition of the present invention comprises about 425 mg of enobritusumab, about 3.06 mg of glacial acetic acid, about 16.15 mg of sodium acetate trihydrate, about 1530 mg of sucrose, about 1.7 mg of PS80, and water, and the pH of the composition is about 5.1. In another alternative embodiment, about 17 mL of the pharmaceutical composition of the present invention comprises about 425 mg of enoblituzumab, about 4.59 mg of glacial acetic acid, about 12.58 mg of sodium acetate trihydrate, about 1530 mg of sucrose, about 1.7 mg of PS80, and water, and the pH of the composition is about 4.6 to about 5.4. In another alternative embodiment, about 17 mL of the pharmaceutical composition of the present invention comprises about 425 mg of enoblituzumab, about 4.59 mg of glacial acetic acid, about 12.58 mg of sodium acetate trihydrate, about 1530 mg of sucrose, about 1.7 mg of PS80, and water, and the pH of the composition is about 5.0.

[0110] In one embodiment, about 20 mL of the pharmaceutical composition of the present invention comprises about 500 mg of enobrituzumab, about 10 mM sodium acetate, about 1800 mg of sucrose, about 2 mg of PS80, and water, and the pH of the composition is about 4.6 to about 5.5. In another embodiment, about 20 mL of the pharmaceutical composition of the present invention comprises about 500 mg of enobrituzumab, about 10 mM sodium acetate, about 1800 mg of sucrose, about 2 mg of PS80, and water, and the pH of the composition is about 5.1. In another embodiment, about 20 mL of the pharmaceutical composition of the present invention comprises about 500 mg of enobrituzumab, about 10 mM sodium acetate, about 1800 mg of sucrose, about 2 mg of PS80, and water, and the pH of the composition is about 5.0.

[0111] In one embodiment, about 20 mL of the pharmaceutical composition of the present invention comprises about 500 mg of enoblituzumab, about 3.6 mg of glacial acetic acid, about 19 mg of sodium acetate trihydrate, about 1800 mg of sucrose, about 2 mg of PS80, and water, and the pH of the composition is about 4.7 to about 5.5. In another embodiment, about 20 mL of the pharmaceutical composition of the present invention comprises about 500 mg of enoblituzumab, about 3.6 mg of glacial acetic acid, about 19 mg of sodium acetate trihydrate, about 1800 mg of sucrose, about 2 mg of PS80, and water, and the pH of the composition is about 5.1. In another embodiment, about 20 mL of the pharmaceutical composition of the present invention comprises about 500 mg of enoblituzumab, about 3.6 mg of glacial acetic acid, about 19 mg of sodium acetate trihydrate, about 1800 mg of sucrose, about 2 mg of PS80, and water, and the pH of the composition is about 4.6 to about 5.4. In one embodiment, about 20 mL of the pharmaceutical composition of the present invention comprises about 500 mg of enoblituzumab, about 5.4 mg of glacial acetic acid, about 14.8 mg of sodium acetate trihydrate, about 1800 mg of sucrose, about 2 mg of PS80, and water, and the pH of the composition is about 4.8.

[0112] In one embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 1,200 mg of enobrituzumab, about 20 mM sodium acetate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 1,200 mg of enobrituzumab, about 20 mM sodium acetate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 4.8. In one embodiment, about 10 mL of the pharmaceutical composition of the present invention comprises about 1,200 mg of enobrituzumab, about 5.2 mg of glacial acetic acid, about 15 mg of sodium acetate trihydrate, about 900 mg of sucrose, about 1 mg of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, about 10 mL of a pharmaceutical composition of the invention comprises about 1,200 mg of enoblituzumab, about 5.2 mg of glacial acetic acid, about 15 mg of sodium acetate trihydrate, about 900 mg of sucrose, about 1 mg of PS80, and water, wherein the pH of the composition is about 4.8.

[0113] In one embodiment, the osmolality of the pharmaceutical composition of the present invention is about 200 to about 400 mOsm / kg·H2O. In another embodiment, the osmolality of the pharmaceutical composition of the present invention is about 225 to about 375 mOsm / kg. In another embodiment, the osmolality of the pharmaceutical composition of the present invention is about 250 to about 360 mOsm / kg. In another embodiment, the osmolality of the pharmaceutical composition of the present invention is about 260 to about 340 mOsm / kg·H2O.

[0114] In certain embodiments, the pharmaceutical composition of the present disclosure is sterile. In one embodiment, the pharmaceutical composition of the present disclosure is non-pyrogenic. The present disclosure further provides an embodiment of the pharmaceutical composition, sealed package, or kit, wherein the water is sterile, non-pyrogenic, distilled water. In another embodiment, the water in the sealed package, kit, or pharmaceutical composition of the present disclosure is Water for Injection, USP, or equivalent thereof.

[0115] In one embodiment, the pharmaceutical composition of the present invention is stable for at least about 3 months at about 25° C. In another embodiment, the pharmaceutical composition of the present invention maintains the monomeric purity of enoblituzumab for at least about 3 months at about 25° C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 5% or less in about 3 months at about 25° C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 3% or less in about 3 months at about 25° C. In another embodiment, the pharmaceutical composition of the present invention maintains the charge heterogeneity profile of enoblituzumab for at least about 3 months at about 25° C. In another embodiment, the decrease of the main charge peak (MCP) of enoblituzumab in the pharmaceutical composition is about 20% or less in about 3 months at about 25° C. In another embodiment, the AV of enoblitutuzumab in the pharmaceutical composition increases by about 20% or less in about 3 months at about 25°C.

[0116] In one embodiment, the pharmaceutical composition of the present invention is stable for at least about 6 months at about 25° C. In another embodiment, the pharmaceutical composition of the present invention maintains the monomeric purity of enoblituzumab for at least about 6 months at about 25° C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 6% or less in about 6 months at 25° C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 5% or less in about 6 months at about 25° C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 3% or less in about 6 months at about 25° C. In another embodiment, the pharmaceutical composition of the present invention maintains the charge heterogeneity profile of enoblituzumab for at least about 6 months at about 25° C. In another embodiment, the loss of MCP of enoblituzumab in the pharmaceutical composition is about 20% or less in about 6 months at about 25° C. In another embodiment, the AV of enoblitutuzumab in the pharmaceutical composition increases by about 20% or less at about 25° C. in about 6 months.

[0117] In one embodiment, the pharmaceutical composition of the present invention is stable at about 2°C to about 8°C for at least about 18 months. In another embodiment, the pharmaceutical composition of the present invention maintains the monomeric purity of enoblituzumab at about 2°C to about 8°C for at least about 18 months. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 5% or less in about 18 months at about 2°C to about 8°C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 4% or less in about 18 months at about 2°C to about 8°C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 3% or less in about 18 months at about 2°C to about 8°C. In another embodiment, the pharmaceutical composition of the present invention maintains the charge heterogeneity profile of enoblituzumab at about 2°C to about 8°C for at least about 18 months. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 10% or less in about 18 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 9% or less in about 18 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition or in the administration solution is about 7% or less in about 18 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition or in the administration solution is about 5% or less in about 18 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblituzumab in the pharmaceutical composition is about 5% or less in about 18 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblitutuzumab in the pharmaceutical composition is about 4% or less over about 18 months at about 2° C. to about 8° C. In another embodiment, the increase in AV of enoblitutuzumab in the pharmaceutical composition is about 3% or less over about 18 months at about 2° C. to about 8° C.

[0118] In one embodiment, the pharmaceutical composition of the present invention is stable at about 2°C to about 8°C for at least about 24 months. In another embodiment, the pharmaceutical composition of the present invention maintains the monomeric purity of enoblituzumab at about 2°C to about 8°C for at least about 24 months. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 5% or less at about 24 months at about 2°C to about 8°C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 4% or less at about 24 months at about 2°C to about 8°C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 3% or less at about 24 months at about 2°C to about 8°C. In another embodiment, the pharmaceutical composition of the present invention maintains the charge heterogeneity profile of enoblituzumab at about 2°C to about 8°C for at least about 24 months. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 10% or less in about 24 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 9% or less in about 24 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 7% or less in about 24 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 5% or less in about 24 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblituzumab in the pharmaceutical composition is about 5% or less in about 24 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblituzumab in the pharmaceutical composition is about 4% or less in about 24 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblitutuzumab in the pharmaceutical composition is about 3% or less at about 2°C to about 8°C in about 24 months.

[0119] In one embodiment, the pharmaceutical composition of the present invention is stable at about 2°C to about 8°C for about 36 months. In another embodiment, the pharmaceutical composition of the present invention maintains the monomeric purity of enoblituzumab at about 2°C to about 8°C for about 36 months. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 5% or less at about 36 months at about 2°C to about 8°C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 4% or less at about 36 months at about 2°C to about 8°C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 3% or less at about 36 months at about 2°C to about 8°C. In another embodiment, the pharmaceutical composition of the present invention maintains the charge heterogeneity profile of enoblituzumab at about 2°C to about 8°C for at least about 36 months. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 10% or less in about 36 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 9% or less in about 36 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 7% or less in about 36 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 5% or less in about 36 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblituzumab in the pharmaceutical composition is about 5% or less in about 36 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblituzumab in the pharmaceutical composition is about 4% or less in about 36 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblitutuzumab in the pharmaceutical composition is about 3% or less at about 2°C to about 8°C in about 36 months.

[0120] In one embodiment, the pharmaceutical composition of the present invention is stable at about 2°C to about 8°C for about 48 months. In another embodiment, the pharmaceutical composition of the present invention maintains the monomeric purity of enoblituzumab at about 2°C to about 8°C for about 48 months. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 5% or less at about 48 months at about 2°C to about 8°C. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 4% or less at about 2°C to about 8°C for about 48 months. In another embodiment, the loss of monomeric purity of enoblituzumab in the pharmaceutical composition is about 3% or less at about 48 months at about 2°C to about 8°C. In another embodiment, the loss of MCP of enoblituzumab in the pharmaceutical composition is about 10% or less at about 48 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 9% or less in about 48 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 7% or less in about 48 months at about 2°C to about 8°C. In another embodiment, the decrease in MCP of enoblituzumab in the pharmaceutical composition is about 5% or less in about 48 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblituzumab in the pharmaceutical composition is about 5% or less in about 48 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblituzumab in the pharmaceutical composition is about 4% or less in about 48 months at about 2°C to about 8°C. In another embodiment, the increase in AV of enoblituzumab in the pharmaceutical composition is about 3% or less in about 48 months at about 2°C to about 8°C.

[0121] III. Containers and kits The invention also provides a container comprising a pharmaceutical composition of the invention. The invention further provides a pharmaceutical pack or kit comprising one or more containers containing a pharmaceutical composition of the invention. In one embodiment, the container is a vial (e.g., a single dose vial). In one embodiment, the pharmaceutical pack or kit of the invention contains a vial (e.g., a single dose vial). In another embodiment, the pharmaceutical pack or kit contains two or more vials.

[0122] In one embodiment, the container (e.g., vial) contains about 5 mL to about 20 mL of the pharmaceutical composition of the present invention. In one embodiment, the container (e.g., vial) contains about 5 mL of the pharmaceutical composition of the present invention containing about 125 mg of enoblituzumab such that the concentration of enoblituzumab is about 25 mg / mL per container. In another embodiment, the container (e.g., vial) contains about 10 mL of the pharmaceutical composition of the present invention containing about 250 mg of enoblituzumab such that the concentration of enoblituzumab is about 25 mg / mL per container. In another embodiment, the container (e.g., vial) contains about 10 mL of the pharmaceutical composition of the present invention containing about 1,200 mg of enoblituzumab such that the concentration of enoblituzumab is about 120 mg / mL per container. In another embodiment, the container (e.g., vial) contains about 17 mL of the pharmaceutical composition of the invention, including about 425 mg of enoblituzumab, such that the concentration of enoblituzumab is about 25 mg / mL per container. In another embodiment, the container (e.g., vial) contains about 20 mL of the pharmaceutical composition of the invention, including about 500 mg of enoblituzumab, such that the concentration of enoblituzumab is about 25 mg / mL per container. It is understood that the container (e.g., vial) may contain an excess volume of the pharmaceutical composition of the invention to ensure sufficient volume to remove up to about 5 mL (125 mg), up to about 10 mL (250 mg or 1,200 mg), up to about 17 mL (425 mg), and up to about 20 mL (500 mg) of enoblituzumab for dose delivery.

[0123] Additionally, one or more other prophylactic or therapeutic agents useful for treating a disease can also be included in the pharmaceutical pack or kit of the invention. Optionally, such one or more containers can be associated with a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, the notice reflecting approval by the agency of manufacture, use, or sale for administration to humans. Optionally, a product label is associated with one or more of the containers, the product label including one or more directions and / or instructions for preparing and administering a dosage solution containing the enoblituzumab composition.

[0124] The present invention provides a kit comprising a pharmaceutical composition of the invention (i.e., an enoblituzumab composition) that can be used in the above-described methods. In the kit, the pharmaceutical composition of the invention (i.e., an enoblituzumab composition) is generally packaged in an airtight container, such as an ampoule, vial, sachet, or other suitable container, which typically indicates the quantity of the ingredient contained therein. The container can be formed of any pharma- ceutically acceptable material, such as glass, resin, plastic, or other suitable material. In one embodiment, the container is a borosilicate glass vial. In another embodiment, the container is a single-dose 5 mL USP Type I borosilicate glass vial. In another embodiment, the 5 mL container contains about 125 mg of enobrituzumab in a volume of 5 mL. In one embodiment, the container is a borosilicate glass vial. In another embodiment, the container is a single-dose 10 mL USP Type I borosilicate glass vial. In another embodiment, the 10 mL container contains about 250 mg of enoblituzumab in a volume of 10 mL. In another embodiment, the container is a single-dose 20 mL USP Type I borosilicate glass vial. In another embodiment, the 20 mL container contains about 425 mg of enoblituzumab in a volume of 17 mL. In another embodiment, the 20 mL container contains about 500 mg of enoblituzumab in a volume of 20 mL. In one embodiment, the container is aseptically filled. In one embodiment, the pharmaceutical composition of the present invention that comprises the kit is supplied as a liquid solution. Such liquid solutions can be stored in the original container at about 2° C. to about 8° C. until ready for administration. However, such solutions can also be stored at room temperature (about 25° C.) for short periods of time. In one embodiment, the pharmaceutical composition of the present invention has a shelf life of at least about 18 months at about 2° C. to about 8° C. In one embodiment, the pharmaceutical composition of the present invention has a shelf life of at least about 24 months at about 2° C. to about 8° C. In one embodiment, the pharmaceutical composition has a shelf life of at least about 36 months at about 2° C. to about 8° C. In one embodiment, the pharmaceutical composition has a shelf life of at least about 48 months at about 2° C. to about 8° C.In other embodiments, the pharmaceutical compositions of the invention have a shelf life of at least about 3 months at 25° C. In other embodiments, the pharmaceutical compositions of the invention have a shelf life of at least about 6 months at 25° C. The kits can further include, in one or more containers, one or more other prophylactic and / or therapeutic agents that can be used to treat cancer, e.g., in prophylactically or therapeutically effective amounts; and / or the kits can further include one or more antibodies, e.g., cytotoxic antibodies, that bind to one or more cancer antigens associated with cancer. In certain embodiments, the other prophylactic or therapeutic agent is a chemotherapeutic agent. In other embodiments, the prophylactic or therapeutic agent is a biotherapeutic agent or a hormonal therapeutic agent.

[0125] The present invention therefore comprises: a) a container containing a pharmaceutical composition described herein; b) optionally, instructions for administering said pharmaceutical composition to a subject in need thereof. A kit is provided, comprising:

[0126] In one embodiment, the container can contain a pharmaceutical composition comprising about 5 mg / mL to about 200 mg / mL of enobrituzumab, about 5 mM to about 30 mM of sodium acetate, about 50 mg / mL to about 130 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.0 to about 6.0. In one embodiment, the container can contain a pharmaceutical composition comprising about 5 mg / mL to about 200 mg / mL of enobrituzumab, about 8 mM to about 24 mM of sodium acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.6.

[0127] In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 20 mg / mL to about 40 mg / mL of enobrituzumab, about 7.5 mM to about 15 mM of sodium acetate, about 50 mg / mL to about 130 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.0 to about 6.0. In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 20 mg / mL to about 40 mg / mL of enobrituzumab, about 8 mM to about 12 mM of sodium acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.5 to about 5.5. In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 20 mg / mL to about 30 mg / mL of enobrituzumab, about 9 mM to about 11 mM of sodium acetate, about 72 mg / mL to about 104 mg / mL of sucrose, about 0.08 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.5 to about 5.5. In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 25 mg / mL of enobrituzumab, about 10 mM of sodium acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.6 to about 5.5. In one embodiment, the container can contain a pharmaceutical composition comprising about 25 mg / mL enobrituzumab, about 10 mM sodium acetate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, wherein the pH of the composition is about 5.1. In another embodiment, the container can contain a pharmaceutical composition comprising about 25 mg / mL enobrituzumab, about 10 mM sodium acetate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, wherein the pH of the composition is about 5.0.In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 60 mg / mL to about 130 mg / mL of enoblituzumab, about 16 mM to about 24 mM of sodium acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.3 to about 5.3.

[0128] In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 60 mg / mL to about 200 mg / mL of enobrituzumab, about 18 mM to about 22 mM of sodium acetate, about 72 mg / mL to about 104 mg / mL of sucrose, about 0.08 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 120 mg / mL of enobrituzumab, about 20 mM of sodium acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 120 mg / mL enobrituzumab, about 20 mM sodium acetate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.8. In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 5 mg / mL to about 200 mg / mL enobrituzumab, about 0.05 mg / mL to about 0.8 mg / mL glacial acetic acid, about 0.5 mg / mL to about 2.0 mg / mL sodium acetate trihydrate, about 50 mg / mL to about 130 mg / mL sucrose, about 0.05 mg / mL to about 0.6 mg / mL PS80, and water, and the pH of the composition is about 4.0 to about 6.0.

[0129] In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 5 mg / mL to about 200 mg / mL of enoblituzumab, about 0.1 mg / mL to about 0.65 mg / mL of glacial acetic acid, about 0.6 mg / mL to about 1.8 mg / mL of sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.6. In one embodiment, the container can contain a pharmaceutical composition, the composition comprising about 20 mg / mL to about 30 mg / mL of enoblituzumab, about 0.1 mg / mL to about 0.35 mg / mL of glacial acetic acid, about 0.6 mg / mL to about 1.2 mg / mL of sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.5 to about 5.5.

[0130] In another embodiment, the container can contain a pharmaceutical composition, the composition comprising about 22.5 mg / mL to about 27.5 mg / mL of enobrituzumab, about 0.1 mg / mL to about 0.35 mg / mL of glacial acetic acid, about 0.6 mg / mL to about 1.2 mg / mL of sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.5 to about 5.5. In one embodiment, the container can contain about 25 mg / mL of enobrituzumab, about 0.18 mg / mL of glacial acetic acid, about 0.95 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 5.4 to about 5.7. In another embodiment, the container can contain about 25 mg / mL enobrituzumab, about 0.18 mg / mL glacial acetic acid, about 0.95 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 5.1. In one embodiment, the container can contain about 25 mg / mL enobrituzumab, about 0.27 mg / mL glacial acetic acid, about 0.74 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.6 to about 5.4. In another embodiment, the container can contain about 25 mg / mL enobrituzumab, about 0.27 mg / mL glacial acetic acid, about 0.74 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 5.0. In one embodiment, the container can contain about 60 mg / mL to about 130 mg / mL enobrituzumab, about 0.4 mg / mL to about 0.65 mg / mL glacial acetic acid, 1.2 mg / mL to about 1.8 mg / mL sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL sucrose, about 0.05 mg / mL to about 0.2 mg / mL PS80, and water, and the pH of the composition is about 4.3 to about 5.3.In one embodiment, the container can contain about 90 mg / mL to about 130 mg / mL of enoblituzumab, about 0.4 mg / mL to about 0.65 mg / mL of glacial acetic acid, about 1.2 mg / mL to about 1.8 mg / mL of sodium acetate trihydrate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, wherein the pH of the composition is about 4.3 to about 5.3.

[0131] In one embodiment, the container can contain about 120 mg / mL enobrituzumab, about 0.52 mg / mL glacial acetic acid, about 1.5 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.4 to about 5.2. In another embodiment, the container can contain about 120 mg / mL enobrituzumab, about 0.52 mg / mL glacial acetic acid, about 1.5 mg / mL sodium acetate trihydrate, about 90 mg / mL sucrose, about 0.1 mg / mL PS80, and water, and the pH of the composition is about 4.8.

[0132] The water in the compositions, containers, sealed packages, and kits of the invention can be sterile, non-pyrogenic, distilled water and can be Water for Injection, USP, or equivalent.

[0133] In one embodiment, the pharmaceutical kit of the present invention or the sealed package of the present invention can include an instructional material. The instructional material included in the pharmaceutical kit of the present invention or the sealed package of the present invention can instruct to administer the provided pharmaceutical composition in combination with additional agents, which can be provided in the same pharmaceutical kit or sealed package or in a separate pharmaceutical kit or separate sealed package. The instructional material can instruct to administer the provided pharmaceutical composition at regular or irregular intervals, such as about once every two weeks, about once every three weeks, about once every four weeks, or more or less frequently. The instructional material can instruct that one container of the provided pharmaceutical composition contains about 25 mg / mL (e.g., 125 mg / 5 mL, 250 mg / 10 mL, 425 mg / 17 mL, or 500 mg / 20 mL) or about 120 mg / mL (e.g., 1,200 mg / 10 mL) of enoblituzumab. The instructional material can instruct to administer at a weight-based therapeutic dose of about 6 mg / kg, about 10 mg / kg, or about 15 mg / kg. The instructional material can instruct to dilute the provided pharmaceutical composition (e.g., in 0.9% sodium chloride or D5W) prior to administration. The instructional material included in the pharmaceutical kit of the invention or the sealed package of the invention can combine any set of such information (e.g., the instructional material can instruct to dilute the enoblituzumab pharmaceutical composition in 0.9% sodium chloride or D5W and administer at a weight-based therapeutic dose of about 6 mg / kg, about 10 mg / kg, or about 15 mg / kg, and to administer said dose at regular or irregular intervals, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, or more or less frequently). The instructional material can instruct regarding the mode of administration of the included pharmaceutical composition, for example, to administer the pharmaceutical composition by intravenous (IV) infusion. The instructional material included in the pharmaceutical kit of the invention or in the sealed package of the invention can instruct regarding the duration or timing of said administration, for example, to administer the included pharmaceutical composition by intravenous (IV) infusion over about 30 minutes, over about 60 minutes, or over 120 minutes, or over a longer or shorter duration.A maximum of 10 minutes of additional infusion time (i.e., 130 minutes total) is allowed to flush the lines.

[0134] In one embodiment, the instructional material of the pharmaceutical kit of the invention instructs to dilute the pharmaceutical composition in 0.9% sodium chloride to obtain a dosing solution, hi another embodiment, the instructional material of the pharmaceutical kit of the invention instructs to dilute the pharmaceutical composition provided in D5W to obtain a dosing solution.

[0135] In one embodiment, the instruction material of the sealed package of the invention instructs to dilute the pharmaceutical composition in 0.9% sodium chloride to obtain a dosing solution. In another embodiment, the instruction material of the sealed package of the invention instructs to dilute the pharmaceutical composition provided in D5W to obtain a dosing solution.

[0136] In one embodiment, the instructional material of the pharmaceutical kit of the invention provides a method of administering a pharmaceutical composition of the invention to a subject in need thereof, the method comprising: a) diluting the pharmaceutical composition in a container in 0.9% sodium chloride to obtain a dosing solution; b) inverting the container to mix the diluted solution; and c) attaching the container containing the dosing solution to a device for administration to the subject. Includes.

[0137] In one embodiment, the instructional material in a sealed package of the invention provides a method of administering a pharmaceutical composition of the invention to a subject in need thereof, said method comprising: a) diluting the pharmaceutical composition in a container in 0.9% sodium chloride to obtain a dosing solution; b) inverting the container to mix the diluted solution; and c) attaching the container containing the dosing solution to a device for administration to the subject. Includes.

[0138] In one embodiment, administration of the dosing solution of the present invention is by intravenous (IV) infusion over a period of about 30 minutes to about 120 minutes, about 30 minutes, about 60 minutes, or about 120 minutes.

[0139] In one embodiment, the instructional material of the pharmaceutical kit of the invention provides a method of administering a pharmaceutical composition of the invention to a subject in need thereof, the method comprising: a) diluting the pharmaceutical composition in D5W in a container to obtain a dosing solution; b) inverting the container to mix the diluted solution; and c) attaching the container containing the dosing solution to a device for administration to the subject. Includes.

[0140] In one embodiment, the instructional material in a sealed package of the invention provides a method of administering a pharmaceutical composition of the invention to a subject in need thereof, said method comprising: a) diluting the pharmaceutical composition in D5W in a container to obtain a dosing solution; b) inverting the container to mix the diluted solution; and c) attaching the container containing the dosing solution to a device for administration to the subject. Includes.

[0141] In one embodiment, the container is an IV bag containing 0.9% sodium chloride. In another embodiment, the container is an IV bag containing D5W. In another embodiment, the container is a syringe containing 0.9% sodium chloride. In another embodiment, the container is a syringe containing D5W.

[0142] In one embodiment, the pharmaceutical composition of the present invention is diluted to provide a therapeutic dose of about 6 mg / kg to about 15 mg / kg of enoblitutuzumab in the dosing solution. In another embodiment, the pharmaceutical composition of the present invention is diluted to provide a therapeutic dose of about 6 mg / kg of enoblitutuzumab in the dosing solution. In another embodiment, the pharmaceutical composition of the present invention is diluted to provide a therapeutic dose of about 10 mg / kg of enoblitutuzumab in the dosing solution. In another embodiment, the pharmaceutical composition of the present invention is diluted to provide a therapeutic dose of about 15 mg / kg of enoblitutuzumab in the dosing solution.

[0143] The instructional material included in the pharmaceutical kit of the invention or in the sealed package of the invention can instruct as to the appropriate or desired use of the included pharmaceutical composition, e.g., to administer a provided pharmaceutical composition for the treatment of cancer, e.g., in a prophylactically or therapeutically effective amount. In one embodiment, the cancers include: adrenal gland cancer, AIDS-related cancer, alveolar soft part sarcoma, anal cancer (including squamous cell carcinoma of the anal canal (SCAC)), bladder cancer, bone cancer, brain and spinal cord cancer, breast cancer (HER2 +breast cancer, including triple-negative breast cancer (TNBC), carotid bulb tumor, cervical cancer (including HPV-associated cervical cancer), chondrosarcoma, chordoma, chromophobe clear cell renal carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, desmoplastic small round cell tumor, ependymoma, endometrial cancer (including unselected endometrial cancer, MSI-high endometrial cancer, dMMR endometrial cancer, and / or POLE exonuclease domain mutation positive endometrial cancer), Ewing's sarcoma, extraskeletal myxoid chondrosarcoma, gallbladder cancer or bile duct cancer (including cholangiocarcinoma, bile duct cancer), gastric cancer cancer), esophagogastric junction (GEJ) cancer, gestational trophoblastic disease, germ cell tumors, glioblastoma, head and neck cancer (including squamous cell carcinoma of the head and neck (SCCHN)), hematologic malignancies, hepatocellular carcinoma, pancreatic islet cell tumors, Kaposi's sarcoma, kidney cancer, leukemia (including acute myeloid leukemia), liposarcoma / malignant lipomatous tumors, liver cancer (including hepatocellular carcinoma (HCC)), lymphoma (including diffuse large B-cell lymphoma (DLBCL) and non-Hodgkin's lymphoma (NHL)), lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)), medulloblastoma, melanoma (uveal melanoma) tumors, including mesothelioma, meningioma, Merkel cell carcinoma, mesothelioma (including mesothelial pharyngeal carcinoma), multiple endocrine neoplasia, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumors, ovarian cancer, pancreatic cancer, papillary thyroid cancer, parathyroid tumor, childhood cancer, peripheral nerve sheath tumor, pharyngeal cancer, pheochromocytoma, pituitary tumor, prostate cancer (including metastatic castration-resistant prostate cancer (mCRPC)), posterior uveal melanoma, renal metastatic cancer, rhabdoid tumor, rhabdomyosarcoma, sarcoma, skin cancer, small round blue cell tumor of childhood (including neuroblastoma, and rhabdomyosarcoma), soft tissue sarcoma, squamous cell carcinoma, stomach cancer, synovial sarcoma, testicular cancer, thymic carcinoma, thymoma, thyroid cancer, urothelial carcinoma, and uterine cancer.

[0144] The instruction material contained in the pharmaceutical kit of the invention or the sealed package of the invention can instruct the pharmaceutical composition to be administered to a cancer selected from the group consisting of: anal cancer, bladder cancer, breast cancer, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, GEJ cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, prostate cancer, skin cancer, and urothelial cancer.

[0145] In one embodiment, the instructional material contained in the pharmaceutical kit or sealed package of the invention instructs administering the pharmaceutical composition for the treatment of anal cancer, hi another embodiment, the anal cancer is SCAC.

[0146] In one embodiment, the instructional material contained in the pharmaceutical kit or sealed package of the invention provides instructions for administering the pharmaceutical composition for the treatment of lung cancer, hi another embodiment, the lung cancer is NSCLC.

[0147] In one embodiment, the instructional material contained in the pharmaceutical kit or sealed package of the invention instructs administering the pharmaceutical composition for the treatment of breast cancer, hi another embodiment, the breast cancer is TNBC.

[0148] In one embodiment, the instructional material contained in the pharmaceutical kit of the invention or in the sealed package of the invention instructs administering the pharmaceutical composition for the treatment of skin cancer. In another embodiment, the skin cancer is melanoma. In another embodiment, the skin cancer is Merkel cell carcinoma.

[0149] In one embodiment, the instructional material contained in the pharmaceutical kit or sealed package of the invention instructs administering the pharmaceutical composition for the treatment of head and neck cancer, hi another embodiment, the head and neck cancer is SCCHN.

[0150] In one embodiment, the instructional material contained in the pharmaceutical kit or sealed package of the invention provides instructions for administering the pharmaceutical composition for the treatment of prostate cancer, hi another embodiment, the prostate cancer is mCRPC.

[0151] In one embodiment, the instructional material contained in the pharmaceutical kit or sealed package of the invention provides instructions for administering the pharmaceutical composition for the treatment of urothelial carcinoma.

[0152] In any of the above embodiments, the instructional material contained in the pharmaceutical kit of the invention or the sealed package of the invention can instruct the pharmaceutical composition to be administered for the treatment of a cancer as described above, wherein the cancer is a metastatic cancer. In some embodiments, the instructional material contained in the pharmaceutical kit of the invention or the sealed package of the invention can instruct the pharmaceutical composition to be administered for the treatment of a cancer as described above, wherein the cancer is a primary cancer.

[0153] The instructional material included in the pharmaceutical kit of the invention or the sealed package of the invention can direct the administration of the pharmaceutical composition for the treatment of a cancer as described above, before, during, or after another treatment for the cancer. In certain such embodiments, the instructional material can direct the administration of the pharmaceutical composition as a neoadjuvant therapy for the treatment of a cancer as described above. In other such embodiments, the instructional material can direct the administration of the pharmaceutical composition as an adjuvant therapy for the treatment of a cancer as described above. In other such embodiments, the instructional material can direct the administration of the pharmaceutical composition as a component of a combination therapy for the treatment of a cancer as described above.

[0154] The instructional material included in the pharmaceutical kit of the invention or the sealed package of the invention can instruct the pharmaceutical composition to be administered for the treatment of a cancer, such as those described above, that expresses B7-H3. The instructional material can further specify a particular assay or expression measurement, e.g., measuring the expression of B7-H3 by immunohistochemistry. The instructional material can further specify that such B7-H3 expression score is determined by a test approved for use by a regulatory agency (e.g., approved by the FDA).

[0155] IV. Method of Administration The pharmaceutical compositions of the present invention can be provided for the treatment, prevention, and amelioration of one or more symptoms associated with a disease, disorder, or infection by administering a therapeutically or prophylactically effective amount of enoblituzumab to a subject. In one embodiment, the pharmaceutical composition is substantially purified (i.e., substantially free of substances that limit the effectiveness of the composition or produce undesirable side effects) as determined by any suitable method. In another embodiment, the subject is an animal, including a mammal, such as a non-primate (e.g., bovine, equine, feline, canine, rodent, etc.) or a primate (e.g., monkey, such as cynomolgus monkey, human, etc.). In one embodiment, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0156] As used herein, a "therapeutically effective amount" of enoblituzumab of the pharmaceutical composition of the present disclosure when used to treat cancer is an amount that can slow the progression of cancer; reduce the number of cancer cells in a body fluid (e.g., blood, peripheral cells, or lymph), tissue, or organ (cytotoxic); maintain the number of cancer cells relatively constant (cytostatic); reduce tumor size, inhibit metastasis, inhibit tumor growth, and / or alleviate one or more of the symptoms of cancer. The therapeutically effective amount of enoblituzumab for use in formulating the pharmaceutical composition of the present disclosure is provided herein and / or can be determined, for example, by a medical professional, taking into account the type of cancer to be treated, the route of delivery, the age, weight, the severity of the subject's symptoms, and the subject's response pattern. As used herein, a "prophylactically effective amount" of enoblituzumab of the pharmaceutical composition of the present disclosure when used to prevent cancer is an amount that can prevent the occurrence or recurrence of cancer, or reduce the risk of the occurrence or recurrence of cancer. As used herein, treating cancer with the pharmaceutical composition, container, sealed package, kit, or method of the disclosure can include, for example, administering a therapeutically or prophylactically effective amount of enoblituzumab to a subject in need thereof.

[0157] Methods of administering the pharmaceutical compositions of the invention (i.e., enoblitutuzumab compositions) include, but are not limited to, parenteral administration (e.g., intravenously). In another embodiment, the pharmaceutical compositions of the invention (i.e., enoblitutuzumab compositions) are administered intravenously. The pharmaceutical compositions of the invention may be administered with other pharmacologic active agents, such as: chemotherapeutic agents, including but not limited to antimetabolite chemotherapeutic agents (including pemetrexed), platinum-based chemotherapeutic agents (including, for example, cisplatin and carboplatin), and taxane-based chemotherapeutic agents (including, for example, paclitaxel and nab-paclitaxel); biologics, including but not limited to antibodies and antibody-like molecules, including those that bind to cancer antigens or antigens on immune cells, such as T cells. Such cancer antigens include, but are not limited to, 5T4, CD19, CD20, CD51, CD123, DR5, EGFR, EpCam, GD2, gpA33, HER2, PD-L1, ROR-1, TAG-72, and / or VEGFR2. Such antigens on immune cells include, but are not limited to, CTLA-4, LAG-3, and PD-1. Numerous antibodies and antibody-like molecules that bind to such cancer antigens or antigens on immune cells have been described, including, but not limited to, bevacizumab, cetuximab, enoblituzumab, flotetuzumab, margetuximab, ofatumumab, panitumumab, retifanlimab, rituximab, tebotelimab, trastuzumab, and the like.

[0158] In one embodiment, the amount of the pharmaceutical composition of the present invention (i.e., enoblitutuzumab composition) is determined using a weight-based dose of enoblitutuzumab to provide a subject with a therapeutically or prophylactically effective amount of enoblitutuzumab. The term "weight-based dose" as used herein refers to the individual amount of enoblitutuzumab administered per unit body weight of the patient, e.g., milligrams of enoblitutuzumab per kilogram of body weight of the subject (mg / kg body weight; abbreviated herein as "mg / kg"). The calculated dose is administered based on the subject's body weight at baseline. Typically, a significant change in body weight (e.g., at least plus or minus about 10% or more) from a baseline or established plateau body weight will prompt a recalculation of the dose. Single or multiple dosages may be administered.

[0159] In certain embodiments, enoblituzumab is administered to a subject in need thereof at a weight-based dose of about 6 mg / kg to about 15 mg / kg. In certain embodiments, enoblituzumab is administered to a subject in need thereof at a dose of about 6 mg / kg. In certain embodiments, enoblituzumab is administered to a subject in need thereof at a dose of about 10 mg / kg. In certain embodiments, enoblituzumab is administered to a subject in need thereof at a dose of about 15 mg / kg. With respect to weight-based doses, the term "about" is intended to refer to a range of ±10% of the stated dose, so that, for example, a dose of about 15 mg / kg would be 13.5 mg / kg, 16.5 mg / kg, or 13.5 mg / kg to 16.5 mg / kg.

[0160] A dose of the pharmaceutical composition of the invention (i.e., a dose of the enoblituzumab composition) can be administered to a subject at periodic intervals over a period of time (a course of treatment) sufficient to encompass at least 2 doses, at least 4 doses, at least 6 doses, at least 12 doses, or at least 24 doses, or more than 24 doses. Such administration of the pharmaceutical composition of the invention at periodic intervals over a period of time can be considered a "course of treatment." For example, a dosage can be administered once every 2 weeks ("Q2W"), once every 3 weeks ("Q3W"), once every 4 weeks ("Q4W"), or for a shorter or longer period of time. Such periodic administration can continue over a period of time, for example, from about 1 to about 52 weeks or for more than 52 weeks. Such a course of treatment can be divided into multiple increments of shorter intervals, for example, from 2 to 8 weeks, each of which is referred to herein as a "cycle," during which a set number of doses are administered. The dosage and / or frequency of administration may be the same or different during each cycle. Factors that may affect the dosing and timing required to effectively treat a subject include, for example, the severity of the subject's disease or disorder, the formulation, route of delivery, previous treatments, overall health, and / or age, and the presence of other diseases in the subject's body. Furthermore, treatment of a subject with a therapeutically effective amount of enoblituzumab can include a single treatment or a series of multiple treatments.

[0161] A "dosing regimen" is the administration of a dosage in which a given dose (or set of a plurality of such doses) is administered to a subject at a given frequency (or set of a plurality of such frequencies) with one or more predetermined periodicities. One dosing regimen of the invention comprises administering to a subject an enoblituzumab composition of the invention Q3W at a dose of about 3 mg / kg. Another dosing regimen of the invention comprises administering to a subject an enoblituzumab composition of the invention Q3W at a dose of about 6 mg / kg. Another dosing regimen of the invention comprises administering to a subject an enoblituzumab composition of the invention Q3W at a dose of about 10 mg / kg. Another dosing regimen of the invention comprises administering to a subject an enoblituzumab composition of the invention Q3W at a dose of about 15 mg / kg.

[0162] In certain embodiments of the invention, it is specifically contemplated that the pharmaceutical composition is administered to a subject at a predetermined frequency or periodicity or within about 1-3 days of such scheduled intervals, such that administration occurs 1-3 days before, 1-3 days after, or on the scheduled dosing date, for example, once every 3 weeks (± 3 days). In such embodiments, the enoblituzumab composition is administered to a subject in a syringe by an infusion pump. In certain embodiments, the enoblituzumab composition is administered by syringe pump infusion according to any of the dosing regimens of the invention for a duration of at least 1 month or more, at least 3 months or more, at least 4 months, at least 6 months or more, or at least 12 months, or more than 12 months. In certain embodiments, the enoblituzumab composition is administered by IV infusion. In certain embodiments, the pharmaceutical composition of the invention is administered by IV infusion, which may be continuous or discontinuous intravenous infusion. In certain embodiments, the enoblitutumab composition is administered by IV infusion according to any of the above-mentioned dosing regimens for a duration (i.e., treatment course) of at least 1 month or more, at least 3 months or more, at least 4 months, at least 6 months or more, or at least 12 months or more. A treatment period of at least 6 months or more, or at least 12 months or more, or until remission of disease or unmanageable toxicity, for example, is observed. In certain embodiments, treatment is continued for a period of time after remission of disease. In certain embodiments, treatment may be interrupted due to illness, adverse events, etc., and is resumed upon resolution, mitigation, or improvement of such illness, adverse events, etc.

[0163] In certain embodiments of the methods of the invention, the pharmaceutical compositions of the invention (i.e., enoblitutuzumab compositions) are diluted in a syringe with a suitable diluent, e.g., 0.9% sodium chloride or D5W, for administration by infusion pump. In certain embodiments, the pharmaceutical compositions of the invention are diluted in an infusion bag with a suitable diluent, e.g., 0.9% sodium chloride or D5W, for administration by IV infusion. Since infusion or allergic reactions can occur, premedication for prevention of such infusion reactions can be utilized and precautions against anaphylaxis can be taken during administration of the antibody.

[0164] V. Administration of Dosage Solutions Comprising Pharmaceutical Compositions The dosing solution containing the pharmaceutical composition (such as the enoblitutuzumab composition of the present invention) is particularly suitable for intravenous administration, for example, by gravity or using a static infusion pump. The enoblitutuzumab dosing solution can be obtained by combining the enoblitutuzumab composition of the present invention with 0.9% sodium chloride or D5W. In certain embodiments, the administration of the therapeutic dosage is over a period of at least about 30 minutes or at least about 60 minutes. In certain embodiments, the administration of the therapeutic dosage is over a period of at least about 120 minutes.

[0165] In some embodiments, a weight-based dose of about 6 mg / kg to about 15 mg / kg is administered to the patient or subject. In one embodiment, a weight-based dose of about 6 mg / kg, about 10 mg / kg, or about 15 mg / kg is administered to the patient or subject. In other embodiments, a weight-based dose of about 6 mg / kg to about 15 mg / kg is administered Q3W. In other embodiments, a weight-based dose of about 6 mg / kg is administered Q3W. In other embodiments, a weight-based dose of about 10 mg / kg is administered Q3W. In other embodiments, a weight-based dose of about 15 mg / kg is administered Q3W.

[0166] In another embodiment, administration of the dose as described above is by IV infusion over at least about 30 minutes, or over at least about 120 minutes. In another embodiment, administration of the dose as described above is by IV infusion over at least about 30 minutes, or over at least about 90 minutes. In another embodiment, administration of the dose as described above is by IV infusion over at least about 30 minutes, or over at least about 60 minutes. In another embodiment, administration of the enoblituzumab dosing solution is by IV infusion over at least about 30 minutes. In another embodiment, administration of the enoblituzumab dosing solution is by IV infusion over at least about 60 minutes. In another embodiment, administration of the enoblituzumab dosing solution is by IV infusion over at least about 120 minutes.

[0167] To form a dosing solution, the pharmaceutical composition (i.e., the enoblitutumab composition of the present invention) can be added to a container, such as an IV bag (nominal volume 100 mL or 250 mL) containing 0.9% sodium chloride or D5W. In another embodiment, the pharmaceutical composition of the present invention can be added to a container, such as a syringe (nominal volume 20 mL) containing 0.9% sodium chloride or D5W. In one embodiment, the pharmaceutical composition of the present invention is gently mixed before being added to the container containing 0.9% sodium chloride or D5W. In one embodiment, the container is an IV bag. In one embodiment, the IV bag is a polyvinyl chloride (PVC) bag, a polyolefin copolymer (polypropylene and polyethylene) bag, a PVC bag containing di-2-ethylhexyl phthalate (DEHP), a polyamide-coated polyolefin bag, or an ethylene vinyl acetate (EVA) bag. In another embodiment, the container is a syringe. In one embodiment, the syringe is a polypropylene syringe. In one embodiment, an in-line filter is used during administration. In one embodiment, the filter has a pore size of 0.2 μm, 5 μm, or 15 μm. In one embodiment, an in-line filter with a pore size of 0.2 μm is used. In one embodiment, the filter is a polyvinylidene fluoride or cellulose acetate filter. In one embodiment, the filter is a polyethersulfone (PES) filter. In some embodiments, a desired volume of a pharmaceutical composition of the present invention can be added to the IV bag or syringe and the dosing solution can be mixed, for example by gentle inversion.

[0168] In one embodiment, the prepared dosing solution is used immediately. In another embodiment, the prepared dosing solution is stored at 25° C. for up to about 4 hours, or at about 2° C. to about 8° C. for up to about 24 hours. In another embodiment, the prepared dosing solution stored at about 2° C. to about 8° C. for up to about 24 hours is stored at room temperature for an equilibration period of about 30 to about 60 minutes prior to administration.

[0169] VI. Uses of the Compositions of the Invention The pharmaceutical compositions, containers, sealed packages, and kits of the invention can be used, e.g., in a therapeutically or prophylactically effective amount, in methods for the treatment of cancer, and in certain embodiments, for the treatment of cancers that express B7-H3. In some embodiments, the methods of the invention comprise administering, e.g., in a therapeutically or prophylactically effective amount, a pharmaceutical composition of the invention to a subject in need thereof for the treatment of cancer. In some embodiments, the cancers treated using the pharmaceutical compositions, containers, sealed packages, or kits of the invention include: adrenal cancer, AIDS-related cancers, alveolar soft part sarcoma, anal cancer (including squamous cell carcinoma of the anal canal (SCAC)), bladder cancer, bone cancer, brain and spinal cord cancer, breast cancer (including HER2 +breast cancer, including triple-negative breast cancer (TNBC), carotid bulb tumor, cervical cancer (including HPV-associated cervical cancer), chondrosarcoma, chordoma, chromophobe clear cell renal carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, desmoplastic small round cell tumor, ependymoma, endometrial cancer (including unselected endometrial cancer, MSI-high endometrial cancer, dMMR endometrial cancer, and / or POLE exonuclease domain mutation positive endometrial cancer), Ewing's sarcoma, extraskeletal myxoid chondrosarcoma, gallbladder cancer or bile duct cancer (including cholangiocarcinoma, bile duct cancer), gastric cancer cancer), esophagogastric junction (GEJ) cancer, gestational trophoblastic disease, germ cell tumors, glioblastoma, head and neck cancer (including squamous cell carcinoma of the head and neck (SCCHN)), hematologic malignancies, hepatocellular carcinoma, pancreatic islet cell tumors, Kaposi's sarcoma, kidney cancer, leukemia (including acute myeloid leukemia), liposarcoma / malignant lipomatous tumors, liver cancer (including hepatocellular carcinoma (HCC)), lymphoma (including diffuse large B-cell lymphoma (DLBCL) and non-Hodgkin's lymphoma (NHL)), lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)), medulloblastoma, melanoma (uveal melanoma) tumors, including mesothelioma, meningioma, Merkel cell carcinoma, mesothelioma (including mesothelial pharyngeal carcinoma), multiple endocrine neoplasia, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumors, ovarian cancer, pancreatic cancer, papillary thyroid cancer, parathyroid tumor, childhood cancer, peripheral nerve sheath tumor, pharyngeal cancer, pheochromocytoma, pituitary tumor, prostate cancer (including metastatic castration-resistant prostate cancer (mCRPC)), posterior uveal melanoma, renal metastatic cancer, rhabdoid tumor, rhabdomyosarcoma, sarcoma, skin cancer, small round blue cell tumor of childhood (including neuroblastoma, and rhabdomyosarcoma), soft tissue sarcoma, squamous cell carcinoma, stomach cancer, synovial sarcoma, testicular cancer, thymic carcinoma, thymoma, thyroid cancer, urothelial carcinoma, and uterine cancer. The instruction material included in the pharmaceutical kit of the invention can instruct the administration of the pharmaceutical composition to a cancer selected from the group consisting of: anal cancer, bladder cancer, breast cancer, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, GEJ cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, melanoma, ovarian cancer, prostate cancer, and urothelial cancer.

[0170] In one embodiment, the pharmaceutical composition, container, sealed package, or kit of the present invention is used for the treatment of anal cancer, hi another embodiment, the anal cancer is SCAC.

[0171] In one embodiment, the pharmaceutical composition, container, sealed package, or kit of the present invention is used for the treatment of lung cancer, hi another embodiment, the lung cancer is NSCLC.

[0172] In one embodiment, the pharmaceutical composition, container, sealed package, or kit of the present invention is used for the treatment of skin cancer. In another embodiment, the skin cancer is melanoma. In another embodiment, the skin cancer is Merkel cell carcinoma.

[0173] In one embodiment, the pharmaceutical composition, container, sealed package, or kit of the present invention is used for the treatment of head and neck cancer, hi another embodiment, the head and neck cancer is SCCHN.

[0174] In one embodiment, the pharmaceutical composition, container, sealed package, or kit of the present invention is used for the treatment of prostate cancer. In another embodiment, the prostate cancer is mCRPC.

[0175] In one embodiment, the pharmaceutical composition, container, sealed package, or kit of the present invention is used for the treatment of urothelial carcinoma.

[0176] In certain embodiments, the pharmaceutical composition, container, sealed package, or kit of the present invention is used for the treatment of a cancer as described above, wherein said cancer is a metastatic cancer. In certain embodiments, the pharmaceutical composition, container, sealed package, or kit of the present invention is used for the treatment of a cancer as described above, wherein said cancer is a metastatic cancer.

[0177] In certain embodiments, the pharmaceutical composition, container, sealed package, or kit of the present invention is used as a neoadjuvant therapy for the treatment of cancer as described above. In certain embodiments, the pharmaceutical composition, container, sealed package, or kit of the present invention is used as an adjuvant therapy for the treatment of cancer as described above. In certain embodiments, the pharmaceutical composition, container, sealed package, or kit of the present invention is used as a component of a combination therapy for the treatment of cancer as described above.

[0178] In a specific embodiment, the pharmaceutical composition, container, sealed package, or kit of the invention is used for the treatment of a cancer as described above, wherein said cancer expresses B7-H3. EXAMPLES

[0179] Having now generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to limit the invention, unless specifically stated.

[0180] Example 1 Development of pharmaceutical compositions containing enoblituzumab A stable antioxidant-free pharmaceutical composition comprising enoblitutuzumab (the "enoblitutuzumab formulation (DP) composition") was prepared as a liquid composition in a vial.

[0181] 1.1. Target Product Profile of Exemplary Enoblituzumab DP Compositions The target product profile of an exemplary enoblitutuzumab DP composition for a 250 mg or 425 mg vial is shown in Table 1 below.

[0182] [Table 1]

[0183] 1.2.Development of Enoblituzumab Drug Product (DP) Composition in 10 mM Acetate Enobrituzumab was initially formulated in 10 mM sodium phosphate, pH 6.1, 0.15 M NaCl and 0.05 mg / mL polysorbate 80 (PS80) (PBS-T), an acceptable formulation for many IgG1 antibodies. However, this condition resulted in a cloudy appearance when the enobrituzumab concentrate was refrigerated (2-8°C). To determine the effect of buffer, pH, excipients, and surfactants on the appearance of the formulation at 2-8°C, various protein concentrations (21.1 mg / mL to 39.4 mg / mL; shown in Table 2) were tested.

[0184] [Table 2]

[0185] The stability of enoblitutuzumab was compared between pH 5.1 (10 mM acetate buffer), pH 5.5 (10 mM acetate buffer), and pH 6.1 (10 mM phosphate buffer) in the presence of sucrose, sodium chloride, and polysorbate 80 (PS80). As shown in Table 2, lowering the pH and / or eliminating NaCl resulted in improved solubility properties of enoblitutuzumab. Furthermore, the flux rates during diafiltration at pH 5.1 and pH 6.1 showed significantly higher exchange efficiency for the pH 5.1 condition. The difference in diafiltration flux was consistent with the high solubility of enoblitutuzumab at pH 5.1. Further evaluation of the enoblitutuzumab concentrate after diafiltration in the presence of 10 mM sodium acetate at pH 5.1 established its suitability and molecular stability, with no observable change in monomer content. This formulation resulted in a clear antibody solution that could be easily filtered through a 0.2 μm membrane. To suppress the formation of subvisible particles that can be induced by agitation of the protein solution, 0.1 mg / mL of PS80 was added to the filtered enoblituzumab. Thus, in this example, 10 mM sodium acetate buffer at pH 5.1 (3 mM glacial acetic acid, 7 mM sodium acetate) and 0.1 mg / mL of PS80 were selected as the formulation buffer for further development.

[0186] 1.2.1. Evaluation of excipients Additionally, studies were conducted to identify excipients that could enhance the stability of enoblituzumab during storage (e.g., refrigerated or frozen). Enoblituzumab formulations at pH 5.1 containing 10 mM sodium acetate and 0.1 mg / mL PS-80 or pH 6.1 containing 10 mM sodium phosphate and 0.1 mg / mL PS-80 were further formulated by the addition of various excipients. One pH 6.1 formulation and seven other pH 5.1 formulations were prepared by adding combinations of sucrose, trehalose, sorbitol, arginine, lysine, glutamine, and NaCl to obtain mixtures with approximately equal osmolality. The enoblituzumab product stability of these formulations was evaluated at different storage temperatures, agitation stress at room temperature, and under freeze-thaw conditions. The eight enoblituzumab formulations tested are shown in Table 3, and the results of the study are provided below.

[0187] 1.2.2. Appearance evaluation First, the impact of selected excipients was evaluated by the appearance of the mixtures at 2-8°C. Solutions of enoblituzumab at pH 5.1 (acetate) or pH 6.1 (phosphate) became cloudy upon addition of 50 mM NaCl, 50 mM arginine, and 3% sucrose (see #5, #6 in Table 3). Other combinations of basic amino acids and 3-6% sucrose also remained hazy after mixing (see #3, #7, #8 in Table 3). A clear appearance was only achieved for the salt-free and arginine-free conditions (see #1, #2, #4 in Table 3).

[0188] [Table 3]

[0189] 1.2.3. Freeze-thaw research A freeze / thaw study was conducted to evaluate the effect of freezing at 80° C. and thawing at 25° C. for five cycles on the stability of enoblituzumab in seven exemplary formulations at pH 5.1 and one exemplary formulation at pH 6.1. Samples were analyzed initially and after one and five cycles for appearance and % aggregates by size-exclusion high performance liquid chromatography ("SE-HPLC"). Cryoprotection is similar for all formulations, except that those containing trehalose at pH 5.1 (#2) and those containing a combination of sucrose-lysine-NaCl at pH 5.1 (#7) showed slightly higher levels of aggregate formation after repeated freeze-thaw cycles. The 9% sucrose formulation was one of the two formulations with the highest compatibility in both appearance and freeze-thaw protection against aggregates among the eight formulations tested. The analytical results are summarized in Table 3.

[0190] The results show that significantly more subvisible particles are formed in the presence of sodium chloride after freeze / thaw. From the freeze / thaw studies, 9% (90 mg / mL) sucrose, 0.01% (0.1 mg / mL) PS80, 10 mM acetate, pH 5.1 was the most stable of the exemplary formulations for enoblituzumab.

[0191] 1.2.4. Aggregate studies Subsequently, accelerated stability studies were performed on enoblituzumab in glass vials at an elevated storage temperature of 37° C., as shown in Table 3. These conditions artificially increased the rate of aggregate formation and fragmentation, which may help differentiate potential stabilizing properties of added excipients. The arginine-sucrose combination (#3) and the four NaCl-containing formulations (#5, #6, #7, #8) appeared to destabilize enoblituzumab at elevated temperatures. Consistent improvements in appearance and stability were achieved with the addition of 9% sucrose (#1) versus other formulations of comparable osmolality. Thus, the aggregate studies also confirmed that the formulation composed of 10 mM sodium acetate, pH 5.1, containing 9% sucrose and 0.1 mg / mL PS80 was the most stable of the exemplary formulations with respect to enoblituzumab.

[0192] 1.3.Development of Enoblituzumab Drug Product (DP) Composition in 20 mM Acetate Studies were conducted to evaluate additional exemplary formulations, particularly antioxidant-free acetate formulations with enoblituzumab concentrations of 60 mg / mL or greater.

[0193] 1.3.1. pH shift analysis For this study, 20 mM sodium acetate buffers with pH between 3.7 and 5.0 were selected to evaluate pH shifts at a relatively high concentration of 60 mg / mL. Briefly, preformulated enoblituzumab was buffer exchanged into 20 mM formulation buffers with starting pHs of 3.7, 4.3, 4.5, 4.8, or 5.0 using dialysis cassettes. The resulting material was then concentrated to 60 mg / mL and sucrose (9% final) and PS80 (0.1% final) were added. pH, protein concentration (Solo-VPE), and percent high molecular weight species (%HMWS) by SE-HPLC were measured to evaluate the pH shift and aggregate levels of each formulation. The results are shown in Table 4.

[0194] [Table 4]

[0195] All formulations were observed to have a pH shift after buffer exchange into the target formulation. The pH shift is more pronounced the further away the pH of the starting buffer is from the molecular pI of 8.65. A shift of 0.8 pH units for a pH buffer starting at pH 3.7 was observed to result in a formulation with a pH of 4.5. When using a starting pH buffer of pH 5.0, the pH shift is reduced to 0.2, which results in a pH of 5.2 in the final formulation. Enoblituzumab >60 mg / mL formulated in 20 mM sodium acetate buffer at a relatively low pH of 4.5 had the lowest %HMWS of 1.7% compared to the formulation condition of pH 5.2, which had the highest %HMWS of 2.0%. The results for %HMWS indicate that there is a slight pH dependency in aggregate formation, with lower %HMWS observed in the lower pH formulations.

[0196] The pH shift effect is observed because enoblituzumab is a highly charged antibody with a pI of pH 8.65 as determined by imaged capillary isoelectric focusing (iCIEF). This study demonstrated that formulations of enoblituzumab, especially those at higher concentrations, are susceptible to pH shifts. The pH shift gradually decreased with increasing pH. Also, aggregate formation is partially pH dependent, as lower % aggregates were observed at lower pH conditions. Thus, the long-term stability of high-concentration enoblituzumab formulations is improved by using a higher buffer concentration (e.g., 20 mM), which can better achieve and maintain optimal pH.

[0197] 1.3.2. Accelerated and stressed thermal studies A short-term stability study was conducted to monitor the stability of enoblituzumab in additional exemplary enoblituzumab formulations under frozen (-60°C to -80°C), normal (2-8°C), accelerated (23-27°C), and stressed (38-42°C) storage conditions. Two 20 mM acetate-high concentration formulations containing 60 mg / mL enoblituzumab and one 10 mM acetate-low concentration formulation containing 25 mg / mL enoblituzumab were evaluated in this study. The formulation components, target protein concentrations, and pH are provided in Table 5. The enoblituzumab formulations were prepared and sterile filtered using 0.22 μM SterileFlip (PVDF) filters before being filled into sterile 2 mL USP Type 1 glass vials. Each vial was stoppered and capped under aseptic conditions. Vials were stored under frozen (-60°C to -80°C), normal (2-8°C), accelerated (23-27°C), and stressed (38-42°C) storage conditions. Enoblituzumab product quality was assessed using visual inspection, protein concentration (UV280nm, using Solo-VPE spectrophotometer), pH, osmolality, subvisible particulates (light obscuration, HIAC, selected time points), % high molecular weight species (%HMW) (SE-HPLC), and charge variant distribution (IE-HPLC). The stability study matrix including time points and storage conditions is summarized in Table 6.

[0198] [Table 5]

[0199] [Table 6]

[0200] The results of the stability studies are summarized in Tables 7-15. All three formulations were observed to be clear, light yellow, and essentially free of visible foreign matter and proteinaceous particles. Protein concentration, pH measured at T=0, and osmolality are shown in Table 7. Enobrituzumab at a concentration of 25 mg / mL formulated in 10 mM sodium acetate at pH 5 (10A50-25) showed no increase in %HMW species for all storage conditions up to 6 months. Enobrituzumab at a higher concentration of 60 mg / mL formulated in 20 mM sodium acetate at pH 4.8 (20A48-60) and 5.1 (20A51-60) showed no increase in %HMW species when stored under frozen (-70±10°C) and normal storage conditions (5±3°C) for up to 6 months (Tables 8 and 9). A small increase in %HMW species was observed for the high concentration (60 mg / mL) formulations under accelerated (25±2°C) and stressed (40±2°C) conditions (Tables 10 and 11). The high concentration formulation at pH 4.8 (20A48-60) showed slightly lower %HMW species formation compared to the high concentration formulation at pH 5.1 (20A51-50). The high concentration formulation at pH 4.8 showed an increase of 0.3% (from 1.1% to 1.4%) after 3 months at 25±2°C and an increase of 0.4% (from 1.1% to 1.5%) after 4 weeks at 40±2°C. In comparison, the high concentration formulation at pH 5.1 showed an increase of 0.4% (from 1.1% to 1.5%) and 0.6% (from 1.1% to 1.7%), respectively, under the same storage conditions.

[0201] The trend of charge variant distribution was similar for all three formulations during 6 months of storage. No significant changes in percent main charge peak (%MCP) were observed when stored up to 6 months at frozen (-70±10°C) and recommended (5±3°C) storage conditions (Tables 12 and 13). However, %MCP decreased from about 32% to about 24% after 3 months under 25±2°C storage conditions (Table 14) and from about 32% to about 16% after 4 weeks under stressed storage conditions at 40±2°C (Table 15). This decrease was accompanied by an increase in both acidic variants (AV) and basic variants (BV). The charge variant data does not indicate a pH or concentration dependency on degradation tendency.

[0202] [Table 7]

[0203] [Table 8]

[0204] [Table 9]

[0205] [Table 10]

[0206] [Table 11]

[0207] [Table 12]

[0208] [Table 13]

[0209] [Table 14]

[0210] [Table 15]

[0211] In summary, this short-term stability study demonstrates the stability of all three exemplary enoblituzumab formulations at both frozen (-60°C to -80°C) and 2-8°C storage conditions, with no significant changes in product quality after 6 months of storage for both molecular weight distribution by SE-HPLC and charge variant distribution by IE-HPLC. The results of this study indicate that the high concentration formulation (60 mg / mL, 20 mM sodium acetate buffer, 9% sucrose, and 0.01% PS80) is slightly more stable when formulated at pH 4.8 compared to pH 5.1 based on %HMWS formation rate at accelerated (25±2°C) and stressed (40±2°C) conditions. Charge variant distribution demonstrated no concentration or pH dependent degradation at accelerated (25±2°C) and stressed (40±2°C) conditions.

[0212] 1.4. Overview of formulation development These formulation development studies demonstrate that enobrituzumab is stable under both frozen (-60°C to -80°C) and conventional (2°C to 8°C) storage conditions and that no significant changes in product quality occurred after 6 months of storage in terms of both molecular weight distribution by SE-HPLC and charge variant distribution by IE-HPLC when formulated in a 10 mM acetate formulation (25 mg / mL enobrituzumab, 10 mM sodium acetate, 9% sucrose, and 0.01% PS80, pH 5.1 ± 0.4) and a 20 mM acetate formulation (60 mg / mL, 20 mM sodium acetate, 9% sucrose, and 0.01% PS80, pH 4.8 ± 0.4).

[0213] These studies also demonstrate that, in contrast to other antibody compositions previously described, enoblituzumab can be formulated in about 10 mM to about 20 mM acetate, an acetate buffer containing sucrose and PS80 at a pH of 4.4 to 5.5, without the use of antioxidants (e.g., histidine, methionine). In particular, these studies support the use of 20 mM acetate, sucrose, and PS80 (e.g., 20 mM sodium acetate, 9% sucrose, and 0.01% PS80, pH 4.8±0.4) as a liquid formulation for a highly concentrated enoblituzumab DP composition. Further studies were also performed on highly concentrated enoblituzumab formulations, as provided in more detail below. Based on these formulation development studies, a first DP composition (25 mg / mL enoblituzumab, 10 mM sodium acetate, 9% sucrose, and 0.01% PS80, pH 5.1±0.4) was defined (referred to herein as "enoblituzumab DP1"), and a second DP composition (25 mg / mL enoblituzumab, 10 mM sodium acetate, 9% sucrose, and 0.01% PS80, pH 5.0±0.4) was defined (referred to herein as "enoblituzumab DP2").

[0214] 1.5. Methods of Supplying Enoblituzumab DP1 Compositions The components of selected enoblituzumab DP1 and DP2 compositions are shown below in Tables 16A and 16B, respectively. The enoblituzumab DP1 and DP2 compositions were supplied in 10 mL or 20 mL Type 1 borosilicate vials as shown in Tables 16A-16B: 250 mg / 10 mL (10 mL vial) or 425 mg / 17 mL (20 mL vial). Both the DP1 (Table 16A) and DP2 (Table 16B) compositions contain 25 mg / mL enoblituzumab, 10 mM sodium acetate, 9% sucrose, and 0.01% PS80, but with different ionic concentrations and slightly different target pH. The DP2 formulation ensures that the correct target pH of 5.0 is achieved and maintained stable over time.

[0215] [Table 16]

[0216] [Table 17]

[0217] Enoblituzumab DP1 and DP2 compositions were provided as sterile, buffered aqueous solutions in 10 mL (250 mg / vial) or 20 mL (425 mg / vial) Type I borosilicate glass vials conforming to USP and Ph.Eur., capped with 20 mm FluroTec® and B2-40 coated butyl rubber stoppers. The nominal content of each vial was 10 mL or 17 mL. Each vial was overfilled with 0.6 mL of liquid. The overfill was included to ensure sufficient volume to withdraw 10 mL (250 mg) and 17 mL (425 mg) of enoblituzumab for dose delivery. Target fill volumes, deliverable volumes, and vial / syringe hold-up volumes were determined by extractable volume testing. The enoblituzumab DP1 and DP2 compositions are clear to slightly opalescent, colorless to pale yellow or pale brown solutions. Some proteinaceous enoblituzumab particles may be present. The enoblituzumab DP compositions supplied as described in this section were used in the dosage compatibility studies described below, as well as the long-term and accelerated stability studies.

[0218] Example 2 IV Administration Compatibility Study of Enoblituzumab DP1 Composition The Enoblituzumab DP1 composition is available in single dose vials and is administered as an intravenous (IV) infusion after dilution in saline (0.9% Sodium Chloride Injection, USP). The dilution is calculated based on the amount to be administered, e.g., for weight-based dosing, the patient's weight and dose are used to calculate the amount. Compatibility has been tested to accommodate a wide range of doses from 0.01 mg / kg to 15 mg / kg.

[0219] 2.1. Overview of compatibility study with enoblituzumab DP1 To prepare for infusion, dilution of the enoblituzumab DP1 solution is performed in a saline-containing syringe or IV administration bag. The infusion solution is administered to the patient from a dose-prepared 0.9% sodium chloride IV bag or syringe using a commercially available IV pump and IV administration tubing set. As described in further detail below, stability and compatibility studies were performed with dose-prepared enoblituzumab dilution and storage at 25° C. for up to 24 hours, as well as IV infusion of enoblituzumab using unfiltered and filtered IV infusion sets over a 120 minute IV infusion period.

[0220] In the initial compatibility study, the enoblituzumab DP composition was diluted in a polypropylene syringe of the same composition as commonly used in clinical practice, or in a polyolefin IV bag of the same composition as commonly used in clinical practice, which were kept at 25° C. The dilution scheme for the test syringes followed a bracketing approach, with two doses (0.0450 mg / mL and 5.59 mg / mL) tested in a 20 mL polypropylene syringe with a small bore IV extension set, representing low and high dose concentrations. The dilution scheme for the test IV bags followed a bracketing approach, with multiple drug concentrations (0.0270 mg / mL, 0.135 mg / mL, and 5.59 mg / mL) tested in a polyolefin IV bag (50 mL and 250 mL size) with a standard IV administration set, representing high and low enoblituzumab dose concentrations. An overview of the bracketing approach and materials used are shown in Table 17.

[0221] [Table 18]

[0222] The structural integrity of enobrituzumab was maintained across all conditions and time points, as assessed by size-exclusion chromatography (SE-HPLC) and protein concentration recovery by UV spectrophotometry. These studies support the stability of enobrituzumab and its suitability for clinical administration when diluted in 0.9% sodium chloride in polypropylene syringes and polyolefin IV bags.

[0223] 2.2. Evaluation of the compatibility of the enoblitutuzumab DP1 composition for use with polypropylene syringes and small bore IV extension sets To evaluate the compatibility and stability of enoblituzumab in 20 mL polypropylene syringes, each of the two test concentrations of enoblituzumab was prepared in multiple syringes and incubated at 25°C.

[0224] Study design Enoblituzumab was diluted in saline to concentrations of 0.045 mg / mL and 5.59 mg / mL in 20 mL polypropylene syringes containing saline (Table 15). The syringes were then held at 25°C for 0, 4, 8, and 24 hours. Control samples not exposed to the polypropylene syringes were prepared in parallel and held at 2-8°C for 0, 4, 8, and 24 hours. Samples were collected from each syringe at the completion of dose preparation (T=0) and at each time point (4, 8, and 24 hours). For each time point, samples were removed from two syringes for analysis. Each syringe was used only for a single time point.

[0225] To evaluate the compatibility and stability of enoblituzumab during passage through a small bore IV extension set (used with a 20 mL syringe), two test concentrations of enoblituzumab were each prepared in four 20 mL syringes and incubated at 25°C for 4-6 hours. The contents of two of the syringes of each concentration were then removed as control samples for the IV extension set study. The remaining syringe was attached to a small bore IV extension set and a syringe pump was used to pass the contents through the extension set over a period of 120 minutes. The entire contents of one syringe were collected in a single container and analyzed. Two administration sets were analyzed for each concentration.

[0226] 2.2.2.Results The results of these studies demonstrate that no significant changes in protein recovery (IgG concentration) and appearance and size distribution (SE-HPLC) were observed for all groups tested following incubation in polypropylene syringes for up to 24 hours or passage through a small bore IV extension set. Recovery of enoblituzumab after incubation in 20 mL syringes for up to 24 hours or passage through an IV extension set was ≥ 97.2%, and the relative amount of IgG monomer (%monomer), aggregates (%HMW), or fragments, clipped antibody forms, and free light or heavy chains (%LMW) did not change significantly.

[0227] Representative results of an in-use compatibility study using polypropylene syringes and small bore IV extension sets, with saline as the dosing mixture, are shown in Tables 18 and 19. At each time point shown (0, 4, 8, and 24 hours), samples were removed from two syringes for analysis. Individual results for each of the two syringes are shown. Each syringe was only used for a single time point and analyzed for protein concentration (IgG % recovery) and structural integrity (by SE-HPLC).

[0228] [Table 19]

[0229] [Table 20]

[0230] Footnotes used in Tables 18 and 19: a IgG % recovery is calculated as the measured IgG concentration of the test article divided by the relevant reference value. The reference value for the control sample was the theoretical test concentration. The reference value for the T=0, T=4, T=8, and T=24 hour samples, or samples after IV plumbing, was the average measured value of the two control samples. b % monomer is calculated as the area of ​​the SE-HPLC monomer peak divided by the sum of all peaks. The % monomer of each test sample should be compared to a control sample at the same dose level. c % HMW - high molecular weight species including dimers and larger forms is calculated as the sum of all SE-HPLC peaks with an apparent molecular weight greater than the IgG monomer divided by the sum of all peaks. The % HMW of each sample is compared to a control sample at the same dose level. d LMW - low molecular weight; species with an apparent molecular weight less than the IgG monomer, including antibody fragments and unbound heavy or light chains. %LMW is calculated as the sum of all SE-HPLC peaks with an apparent molecular weight less than the IgG monomer divided by the sum of all peaks. The %LMW of each sample is compared to a control sample at the same dose level.

[0231] 2.3. Evaluating the compatibility of the enoblitutuzumab DP composition for use with polyolefin IV bags and standard IV administration sets To evaluate the compatibility and stability of the enoblituzumab DP1 compositions in polyolefin IV bags, 50 mL and 250 mL IV bags were prepared with low and high concentrations of the enoblituzumab DP1 compositions (Table 16A), respectively, and incubated at 25° C.

[0232] Study design The enoblitutumab DP1 composition was diluted to three concentrations (0.027 mg / mL, 0.135 mg / mL, and 5.59 mg / mL) in polyolefin IV bags containing saline (50 mL or 250 mL). Two test bags of each size and concentration were prepared on separate days (Study 1 and Study 2). The IV bags were then held at 25°C for 0, 4, 8, and 24 hours. Control samples were prepared in parallel and held at 2-8°C for 0, 4, 8, and 24 hours. At each time point, samples were removed from each IV bag for analysis.

[0233] The low concentration tested in the IV bag was based on an estimated low dose of 6.75 mg, which corresponds to a 45 kg clinical subject receiving a dose level of 0.15 mg / kg. The low concentrations tested were 0.0270 mg / mL in the 250 mL IV bag and 0.135 mg / mL in the 50 mL IV bag, respectively. The high concentration tested was based on an estimated high dose of 1800 mg, which corresponds to a 120 kg clinical subject receiving a dose level of 15 mg / kg. This dose was tested in a 250 mL IV bag to obtain a final concentration of 5.59 mg / mL (72.0 mL of the 25 mg / mL formulation was added to an IV bag containing 250 mL of saline). This concentration of 5.59 mg / mL was also tested as the upper limit concentration in the 50 mL IV bag.

[0234] Simulation of infusion through a standard IV tubing set was accomplished by attaching the tubing set to the IV bag after completion of a 4-6 hour incubation of the diluted enoblituzumab DP composition in the IV bag. At the start of the simulated infusion, a control sample (5 mL) was removed directly from the IV bag and the remaining infusion solution was passed through the tubing set for approximately 120 minutes. The contents of one IV bag were collected in a single sample container and analyzed. Each of the three concentrations was tested in duplicate on separate days (Study 1 and Study 2) using both unfiltered and filtered (sterile non-pyrogenic low protein binding polyethersulfone (PES) 0.2 μM in-line filter) IV administration sets.

[0235] 2.3.2.Results The results of these studies demonstrate that no significant changes in protein recovery (IgG concentration) and appearance and size distribution (SE-HPLC) were observed for all groups tested following incubation in saline in polyolefin IV bags for up to 24 hours or with passage through a standard IV extension set. Recovery of enoblituzumab after incubation in IV bags for up to 24 hours or passage through an IV extension set (unfiltered or filtered; 120 minutes) was ≥85.9% and ≥95.2%, respectively, and the relative amount of IgG monomer (%monomer), aggregates (%HMW), or fragments, clipped antibody forms, and free light or heavy chains (%LMW) did not change significantly.

[0236] Representative results of an in-use compatibility study using polyolefin IV bags and a standard IV extension set, with saline as the dosing mixture, are shown in Tables 20-22. At each time point indicated (0, 4, 8, and 24 hours), samples were removed from the IV bag for analysis. Within each study (Study 1 and Study 2), a single bag was prepared at each test concentration from which samples were removed for T=0, 4, 8, and 24 hours. Each sample was used only for a single time point and analyzed for protein concentration (IgG % recovery) and structural integrity (by SE-HPLC).

[0237] [Table 21]

[0238] [Table 22]

[0239] [Table 23]

[0240] Footnotes used in Tables 20-22: a IgG % recovery is calculated as the measured IgG concentration of the test article divided by the relevant reference value. The reference value for the control samples was the theoretical test concentration. The reference values ​​for the T=0, T=4, T=8, and T=24 hour samples or samples after IV plumbing were the measured values ​​of the control samples from the same study (1 or 2). b % monomer is calculated as the area of ​​the SE-HPLC monomer peak divided by the sum of all peaks. The % monomer of each test sample should be compared to a control sample at the same dose level. c % HMW - high molecular weight species including dimers and larger forms is calculated as the sum of all SE-HPLC peaks with an apparent molecular weight greater than the IgG monomer divided by the sum of all peaks. The % aggregates for each sample should be compared to control samples at the same dose level. d LMW - low molecular weight; species with an apparent molecular weight less than the IgG monomer, including antibody fragments and unbound heavy or light chains. %LMW is calculated as the sum of all SE-HPLC peaks with an apparent molecular weight less than the IgG monomer divided by the sum of all peaks. The %LMW of each sample should be compared to a control sample at the same dose level.

[0241] 2.3.3. Conclusions of the compatibility study of Enoblituzumab DP composition The enoblituzumab DP1 composition was shown to be compatible with saline solutions in 20 mL polypropylene syringes at concentrations ranging from 0.05 to 5.6 mg / mL and with saline solutions in polyolefin IV bags at concentrations ranging from 0.03 to 5.6 mg / mL. The enoblituzumab DP composition was also shown to be compatible with small bore IV extension sets and standard IV administration sets. These results support an enoblituzumab IV solution administration time of 120 minutes and storage of the IV bag preparation for up to 6 hours at room temperature and 24 hours at 2-8°C. These results further support the use of a 0.2 μM in-line PES filter for intravenous infusion of enoblituzumab.

[0242] Example 3 Long-term and accelerated stability studies of Enoblituzumab DP1 formulation Long-term and accelerated stability studies were conducted for enoblituzumab DP1 compositions in stoppered 10 mL or 20 mL glass vials. Stability was evaluated for enoblituzumab DP1 compositions stored at recommended conditions of 2-8°C for up to 48 months and at accelerated conditions of 23-27°C for up to 6 months.

[0243] Experimental Design A summary of the studies performed and the intervals typically evaluated at storage conditions of 2-8°C and 23-27°C are provided in Tables 23A and 23B, respectively. These studies were performed on 17 different lots of enoblituzumab DP1 composition. The majority of the studies were performed with vials in an upright position and with vials that were inverted at least once.

[0244] [Table 24]

[0245] [Table 25]

[0246] Abbreviations used in Tables 23A-23B: CE-SDS = capillary electrophoresis in the presence of sodium dodecyl sulfate; SE-HPLC = size-exclusion high performance liquid chromatography; SDS-PAGE = sodium dodecyl sulfate polyacrylamide gel electrophoresis; IE-HPLC = ion-exchange high performance liquid chromatography; NS = not scheduled (indicating that analysis is not required at this point).

[0247] 3.2.Results The results of all testing on representative lots of enoblituzumab DP composition stored at 2-8° C. for 48 months and at 25° C. for 6 months are shown in Tables 24A-24B and 25, respectively. Further details regarding assay potency, purity, and protein stability (monomer and acidic and basic variants) are provided in the summary below.

[0248] [Table 26]

[0249] [Table 27]

[0250] [Table 28]

[0251] Abbreviations used in Tables 24A-24B and Table 25: Mono = monomer, HMW = high molecular weight species, LMW = low molecular weight species; MCP = main charge peak, AV = acidic variant, BV = basic variant; SO = slightly milky; PY = pale yellow; C = clear; FNP = essentially free of visible foreign particles; FPP = essentially free of visible proteinaceous particles; CPP = contains visible proteinaceous particles; P = particles; NS = not scheduled, indicating that analysis is not required at this point; NA = data not obtained due to technical error; NG = no growth.

[0252] Stability data for all lots of the enoblituzumab DP1 composition investigated were within acceptable limits over 36-48 months at the intended long-term storage conditions of 2-8°C, with the exception of subvisible particulates. Subvisible particulates (P ≥ 2 μm and P ≥ 10 μm) increased in some lots, beginning around the 12th month of storage at 2-8°C. No further changes beyond analytical procedure variability were observed for other monitored parameters.

[0253] At accelerated storage conditions of 25±2°C, all lots investigated were within acceptable limits over 6 months. A slight reduction was observed in potency (B7-H3 binding) and purity by SE-HPLC. These changes in potency and purity under accelerated conditions were not unexpected for the protein and these results were well within acceptable limits. Homogeneity by IE-HPLC showed a moderate decrease in monomeric purity and a moderate increase in acidic variants in some lots, including the representative lot. The acidic variants contain mainly deamidated products. No changes beyond the variability of the analytical procedure were observed for any other parameters monitored, demonstrating the robust stability of the enoblituzumab DP1 composition.

[0254] 3.3. Conclusions regarding stability The above analysis of quantitative data from methods to demonstrate stability of multiple lots of the Enoblituzumab DP1 composition supports a shelf life of at least 24 months at recommended storage conditions of 2-8° C. The representative stability data presented in Tables 24A-24B and Table 25 also show that all other tests, both qualitative and semi-quantitative or non-quantitative, remained within acceptable limits over at least 24 months, supporting a shelf life of at least about 24 months, with an upper limit of at least about 36 to at least about 48 months.

[0255] Example 4 Stability studies on pharmaceutical compositions containing high concentrations of enoblituzumab Stable antioxidant-free pharmaceutical compositions were prepared containing high concentrations of enoblitutuzumab in liquid compositions. Enoblitutuzumab was formulated at 60 mg / mL or 120 mg / mL in 20 mM sodium acetate, 9% sucrose, and 0.01% PS80 at pH 4.8 (Ac60, Ac120). Additionally, enoblitutuzumab was formulated at 120 mg / mL in 20 mM histidine hydrochloride (histidine-HCl), 9% sucrose, and 0.01% PS80 at pH 5.4 (His120) to examine the effect of histidine on appearance and stability.

[0256] 4.1.Appearance evaluation The effect of high concentrations of enoblituzumab, acetate, and histidine-HCl buffer, and pH (4.8 and 5.4) was evaluated by mixture appearance at 2-8°C and 25°C. The results of these studies are shown in Tables 26 and 27. Enoblituzumab product quality was evaluated by visual inspection and subvisible particulates. A clear appearance was achieved after up to 3 months of storage at 2-8°C for enoblituzumab 60 mg / mL formulated in acetate buffer (Ac60) and enoblituzumab 120 mg / mL formulated in acetate buffer (Ac120) or 120 mg / mL formulated in histidine-HCl buffer (His120) (Table 26). The histidine-HCl formulations were more milky white than the acetate formulations after 1 month of storage at 25°C (Table 27). Visual observations in this study indicate that low pH acetate buffer is a good liquid formulation for enoblituzumab.

[0257] [Table 29]

[0258] [Table 30]

[0259] 4.2. Short-term stability study A short-term stability study was conducted to monitor the stability of enoblitutuzumab in high-concentration enoblitutuzumab formulations under normal (2-8°C), accelerated (25°C), and stressed (40±2°C) storage conditions. Enobrituzumab product quality was assessed using % high molecular weight species (%HMW) (SE-HPLC), and charge variant distribution (IE-HPLC). The results of this stability study are summarized in Tables 28-33. Molecular weight analysis for samples stored at 2-8°C (Table 28) showed that the % monomer decreased by approximately 0.6-0.9% over 3 months. A decrease of approximately 2.4-3.0% in the % monomer was observed at the accelerated storage condition at 25°C (Table 29). A larger decrease in the % monomer was observed at the stressed storage condition at 40°C (Table 30). The difference in percent monomer for samples stored at 2-8°C was not significant between the 60 mg / mL and 120 mg / mL acetate formulations at pH 4.8 and the 120 mg / mL histidine formulation at pH 5.4, as shown by SEC.

[0260] [Table 31]

[0261] [Table 32]

[0262] [Table 33]

[0263] The charge variant distribution for each formulation stored at 2-8°C, 25°C, and 40°C are shown in Tables 31, 32, and 33, respectively. Overall, the change in % main charge peak was not significant at normal storage conditions at 2-8°C. Under accelerated storage conditions at 25°C, the % main charge peak decreased by about 3.5%-4.5% at a concentration of 120 mg / mL. Under stressed storage conditions at 40°C, a larger decrease in % main charge peak was observed. No clear trends were observed for % acidic variant (AV) and % basic variant (BV) at any of the conditions tested (2-8°C, 25°C, and 40°C).

[0264] [Table 34]

[0265] [Table 35]

[0266] [Table 36]

[0267] In summary, these short-term stability studies demonstrate that enoblituzumab is stable at concentrations as high as 60 mg / mL and 120 mg / mL when formulated in 20 mM acetate buffer with 9% sucrose and 0.1% PS80 at pH 4.8, with no significant changes in product quality in terms of both molecular weight distribution by SE-HPLC and charge variant distribution by IE-HPLC after 3 months of storage under normal (2-8°C) and accelerated (25°C) storage conditions.

[0268] Example 5 Materials and Methods 5.1.A 280 Protein concentration by The protein concentration of enoblituzumab was determined by measuring the absorbance of the sample in a cuvette using a UV spectrophotometer or by a SoloVPE system (SoloVPE variable pathlength UV system from C Technologies, Inc.).

[0269] For the cuvette method, protein concentration was calculated using the following formula: Protein concentration (mg / mL) = [(corrected A 280 ) / ε]×DF where ε is the extinction coefficient and DF is the dilution factor of the sample preparation.

[0270] The SoloVPE system employs the Slope Spectroscopy method, which is based on the Beer-Lambert law and the slope obtained from linear regression of absorbance measurements at 280 nm performed at multiple path lengths. Protein concentration was calculated using the following Slope Spectroscopy equation: Protein concentration (mg / mL) = c = M / ε where c is the concentration, M is the slope of the regression line, and ε is the extinction coefficient calculated based on the amino acid sequence of enoblituzumab [1.43 (mg / mL)]. -1 cm -1 ].

[0271] 5.2. Invisible Particles by HIAC Liquid Particle Counting USP <788> and Ph.Eur.2.9.19 were used to detect, size, and count subvisible particulate matter in the formulation. An electronic liquid particle counting system with a light obscuration sensor is employed. Particles are counted in three size ranges, ≥ 2 μm (characterization information only), ≥ 10 μm, and ≥ 25 μm, using an electronic liquid particle counting system with a light obscuration sensor (HIAC). Ten vials (10 mL / vial) of the formulation are pooled for analysis.

[0272] 5.3.Appearance The appearance is USP <1> The solutions were visually evaluated in front of both white and black backgrounds under visible light meeting the minimum intensity requirements according to Ph.Eur. 2.2.2, and Ph.Eur. 2.9.20. Aliquots of samples were evaluated in clear glass vials. Attributes examined included solution color and solution clarity. The degree of coloration was determined using Ph.Eur. certified color standards. The degree of clarity was determined using Ph.Eur. certified reference suspension standards.

[0273] 5.4.pH Test The pH of the solution was measured according to the official method [USP <791> The pH was measured potentiometrically using a calibrated pH meter in accordance with [Russian Pharmacopoeia, Ph.Eur.2.2.3]. Prior to testing the samples, the pH meter was three-point calibrated using certified pH standards, starting with a pH 7 buffer standard, then a pH 4 buffer standard, and then a pH 10 buffer standard. Following calibration, the suitability of the system was checked using two certified pH buffers, pH 5 and pH 8.

[0274] 5.5. Monomer Purity by Size Exclusion High Performance Liquid Chromatography (SE-HPLC) Size-exclusion high performance liquid chromatography (SE-HPLC) was used as a measure of product purity and to measure impurities, especially IgG aggregates. The assay includes an enoblituzumab reference standard as a control for the identity of the IgG monomer peak and suitability of the system. Samples are injected onto the SE-HPLC column and eluted isocratically with sodium phosphate / sodium sulfate buffer. Eluted protein was detected using ultraviolet (UV) absorbance at 280 nm. The reportable result was product purity, calculated as the area percent of the product monomer peak (compared to all peaks minus excipient peaks). Also reported were the total percent of all species with an apparent molecular weight greater than the IgG monomer (referred to as high molecular weight species, or HMW), the percent of dimers (a potential component of the HMW species), and the total percent of all species with an apparent molecular weight less than the IgG monomer (referred to as low molecular weight species, or LMW).

[0275] 5.6. Charge Heterogeneity and Identity by IE-HPLC The charge heterogeneity and identity of enobrituzumab was assessed by ion-exchange high performance liquid chromatography (IE-HPLC). The assay includes an enobrituzumab reference standard as a control for identity and system suitability. Samples are injected onto a Thermo WCX-10 column or equivalent and eluted with a salt gradient at constant pH. Eluted protein was detected using ultraviolet (UV) absorbance at 280 nm. Reportable results were the main peak % area (percent of all detected peaks excluding buffer / excipient peaks), as well as the total % area of ​​all acidic variants (AV; or APG, i.e., acidic peak group: peaks eluting before the main peak) and the total % area of ​​all basic variants (BV; or BPG, i.e., basic peak group: peaks eluting after the main peak).

[0276] 5.7. Charge Heterogeneity and Identity by cIEF Alternatively, the charge heterogeneity and identity of enobrituzumab can be assessed by capillary isoelectric focusing (cIEF). For example, cIEF can be performed using an iCE3 system (ProteinSimple) with an Alcott 720NV autosampler. For such analysis, enobrituzumab reference standards and test article samples, containing carrier amphoteric and pI markers, are prepared and loaded into a capillary cartridge for analysis. Electrolyte tanks at each end of the capillary are filled with anolyte and catholyte. A voltage is applied and the sample is focused at the pI of the sample. A camera takes UV light absorption images of the entire capillary column at frequent regular intervals (e.g., every 30 seconds), allowing real-time monitoring of the focusing steps described above. The resulting separation pattern images are captured and analyzed with chromatography data system software. The electrophoretic profile of the test article is compared to that of the reference standard. Reportable results from this assay are the average main charge peak % area, the average acidic variant % area, and the average basic variant % area of ​​duplicate preparations.

[0277] To confirm identity where necessary, within a given sample set, the pI of the major peak of the test article should be within 0.5 pI units of the pI of the major peak of the enoblituzumab reference standard, and the profile of the test article should be qualitatively comparable to that of the reference standard.

[0278] 5.8 Purity by reduced and non-reduced CE-SDS and LDS Reduced and non-reduced sodium dodecyl sulfate capillary electrophoresis (CE-SDS) or sodium lauryl sulfate capillary electrophoresis (CE-LDS) provide quantitative information on the purity of the product and qualitative information on the nature of impurities, adducts, product fragments, and covalent species. Samples for the reduced method were denatured and reduced by heating in SDS sample buffer containing the reducing agent 2-mercaptoethanol (βME). Samples were then electrophoresed using a Sciex PA800 / PA800 Plus capillary electrophoresis system (formerly Beckman Coulter and AB Sciex). Test articles and reference standard samples are loaded into capillary cartridges and product purity is measured by UV detection (220 nm). The reportable result for the test article is % purity, defined as the sum of the relative percentages of the velocity-corrected peak areas corresponding to the heavy and light chains, which was reported to the nearest 0.1%. For the non-reduced method, samples were not reduced and the analysis was performed similarly to the reduced samples. The % purity was defined as the area under the peak of intact IgG molecules observed on the profile.

[0279] 5.9. Purity by non-reducing SDS-PAGE Non-reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) provides quantitative information regarding product purity and qualitative information regarding the nature of impurities, adducts, product fragments, and covalently bound species. Samples were mixed with SDS-PAGE sample buffer without reducing agents. Samples were then electrophoresed using polyacrylamide gradient gels. Two concentrations of samples were loaded onto the gel for electrophoresis: a "low" load was used for quantification and a "high" load was used for qualitative comparison of the test article and reference standard. Each test article was analyzed individually on a single gel, and each gel also contained low and high loads of the enoblituzumab reference standard. After completion of electrophoresis, the gels were stained using Coomassie Blue dye and subsequently destained. The stained gels were scanned and analyzed using a digital imager and densitometry software. The area % of each visible band relative to the total area of ​​all visible bands was calculated. The reportable result was product purity, defined as the sum of the area percent of all bands (in the "low" load lane) that represented intact monomeric IgG. The area percent of a band was calculated relative to the total area of ​​all visible bands.

[0280] 5.10. Potency by B7-H3 Binding ELISA Potency was assessed using an indirect enzyme-linked immunosorbent assay (ELISA) to quantify the binding activity of enoblituzumab to B7-H3. Recombinant human B7-H3 was coated onto the solid phase (96-well assay plate). Enoblituzumab samples were allowed to bind to the immobilized B7-H3. Dilution series of the test article and enoblituzumab reference standard were tested in this manner to generate a dose-response curve. An alkaline phosphatase (AP)-conjugated anti-human kappa antibody was then added and allowed to bind to the enobrituzumab-B7-H3 complex. Quantitation of the bound AP-conjugated antibody was achieved by the addition of 4-methylumbelliferyl phosphate (4-MUP) substrate. Dephosphorylation of the added 4-MUP substrate by the AP-conjugated antibody yields the highly fluorescent and stable product 4-methylumbelliferone, which is measured using a fluorescent microplate reader. The level of fluorescent signal was proportional to the amount of enoblituzumab captured. The data was fitted to a four-parameter model to describe the fluorescent signal as a function of enoblituzumab concentration. The reportable results, i.e., the potency of the test article compared to the enoblituzumab reference standard, were calculated using the following formula: Relative potency = 100% × EC 50 B7‐H3 reference standard / EC 50 Test Article

[0281] 5.11. Potency and Identity by FcgRIIIa Binding ELISA The potency of the Fc domain was evaluated using an indirect competitive enzyme-linked immunosorbent assay (ELISA) that quantifies the binding activity of enoblituzumab to Fcγ reporter subtype IIIa (FcγRIIIa), also known as CD16a. Quantitation of binding of enoblituzumab test article Fc to FcγRIIIa was measured by its ability to compete with the binding of a biotin-labeled enoblituzumab competitor (enoblituzumab-Bt). To perform this assay, a solid phase (96-well assay plate) was coated with soluble recombinant human FcγRIIIa. A dilution series of enoblituzumab test article in a fixed concentration of enoblituzumab-Bt was allowed to bind to the immobilized FcγRIIIa. A dilution series of the test article and enoblituzumab reference standard were analyzed in this manner on the same assay plate to generate a dose-response curve. Detection of bound enobrituzumab-Bt was achieved by the addition of alkaline phosphatase conjugated to streptavidin (streptavidin-AP) followed by colorimetric AP substrate. The intensity of the color signal (absorbance) was measured using a microplate reader. The level of color signal was proportional to the amount of bound enobrituzumab-Bt. The data were fitted to a four-parameter model to describe the absorbance signal as a function of enobrituzumab concentration. The reportable result, i.e. the potency of the test article compared to the enobrituzumab reference standard, was calculated using the following formula: Relative potency = 100% × EC 50 Enoblituzumab Reference Standard / EC 50 Test Article

[0282] Osmolality Osmolality can be calculated from the USP <785> The measurements were performed using a freezing point depression osmometer using the method defined in [Ph.Eur.2.2.35]. NIST traceable standards were used to calibrate each measurement. The suitability of the system was determined prior to the measurement of the test articles by measuring the NIST traceable standards.

[0283] 5.13. Sterility Sterility, USP <71> and was tested using the method defined in Ph.Eur.2.6.1.

[0284] All publications and patents mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0285] The present disclosure is not limited with respect to the specific embodiments described in this application. As will be apparent to those skilled in the art, numerous modifications and variations can be made without departing from the spirit and scope of the present disclosure. In addition to those recited in this disclosure, functionally equivalent methods and compositions within the scope of the present disclosure will be apparent to those skilled in the art from the above description. Such modifications and variations are intended to be included within the scope of the present disclosure and / or the scope of the appended claims. It is understood that the present disclosure is limited to specific methods, compounds, or compositions, which may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting.

Claims

1. a) About 5 mg / mL to about 200 mg / mL of enoblituzumab; b) Acetate; c) Sucrose; d) Polysorbate 80 (“PS80”); and e) Water A pharmaceutical composition comprising the same.

2. The pharmaceutical composition according to claim 1, wherein the acetate comprises sodium acetate and is present at a concentration of about 5 mM to about 30 mM.

3. The composition is: a) Comprising about 5 mM to about 30 mM of acetate, about 50 mg / mL to about 130 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.0 to about 6.0; or b) Comprising about 8 mM to about 24 mM of acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.6 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.6; or c) Comprising about 16 mM to about 24 mM of acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.3 to about 5.3; or d) Comprising about 8 mM to about 12 mM of acetate, about 72 mg / mL to about 108 mg / mL of sucrose, about 0.05 mg / mL to about 0.2 mg / mL of PS80, and water, and the pH of the composition is about 4.5 to about 5.5; or e) Comprising about 10 mM of acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.6 to about 5.5; or f) Comprising about 20 mM of acetate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.2, the pharmaceutical composition according to claim 1 or 2.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the acetate comprises glacial acetic acid at a concentration of about 0.1 mg / mL to about 0.65 mg / mL and sodium acetate trihydrate at a concentration of about 0.6 mg / mL to about 1.8 mg / mL.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the concentration of the enoblituzumab is 5 mg / mL to about 60 mg / mL.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pH of the composition is about 4.6 to about 5.

5.

7. The composition contains about 25 mg / mL of enoblituzumab, about 0.18 mg / mL of glacial acetic acid, about 0.95 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.7 to about 5.

5. The pharmaceutical composition according to any one of claims 1 to 6.

8. The composition contains about 25 mg / mL of enoblituzumab, about 0.27 mg / mL of glacial acetic acid, about 0.74 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.6 to about 5.

4. The pharmaceutical composition according to any one of claims 1 to 6.

9. The composition contains about 120 mg / mL of enoblituzumab, about 0.52 mg / mL of glacial acetic acid, about 1.5 mg / mL of sodium acetate trihydrate, about 90 mg / mL of sucrose, about 0.1 mg / mL of PS80, and water, and the pH of the composition is about 4.4 to about 5.

2. The pharmaceutical composition according to any one of claims 1 to 6.

10. The composition does not contain an antioxidant. The pharmaceutical composition according to any one of claims 1 to 9.

11. The composition has a shelf life of at least about 18 months at about 2°C to about 8°C. The pharmaceutical composition according to any one of claims 1 to 9.

12. The weight osmolality of the composition is from about 200 to about 400 mOsm / kg·H ２ O, and the pharmaceutical composition according to any one of claims 1 to 11.

13. The composition maintains the monomer purity of the enoblituzumab at about 25°C for at least about 3 months. The pharmaceutical composition according to any one of claims 1 to 12.

14. The composition maintains the heterogeneity profile of the enoblituzumab at 25°C for at least about 3 months. The pharmaceutical composition according to any one of claims 1 to 13.

15. A container containing the pharmaceutical composition according to any one of claims 1 to 14.

16. The container contains about 10 mL of the pharmaceutical composition, The volume is: a) about 250 mg of enoblituzumab; b) about 10 mM of sodium acetate c) about 900 mg of sucrose; d) about 1 mg of PS80; and e) water and the pH of the composition is about 4.6 to about 5.

5. The container according to claim 15.

17. The container contains about 10 mL of the pharmaceutical composition, The volume is: a) about 250 mg of enoblituzumab; b) about 1.8 mg of glacial acetic acid c) about 9.5 mg of sodium acetate trihydrate; d) about 900 mg of sucrose; e) about 1 mg of PS80; and f) water comprising, wherein the pH of the composition is from about 4.7 to about 5.5, the container according to claim 15.

18. The container contains about 17 mL of the pharmaceutical composition, wherein the volume is: a) about 425 mg of enobrutinib; b) about 10 mM; c) about 1530 mg of sucrose; d) about 1.7 mg of PS80; and e) water comprising, wherein the pH of the composition is from about 4.6 to about 5.4, the container according to claim 15.

19. The container contains about 17 mL of the pharmaceutical composition, wherein the volume is: a) about 425 mg of enobrutinib; b) about 3.06 mg of glacial acetic acid; c) about 16.15 mg of sodium acetate trihydrate; d) about 1530 mg of sucrose; e) about 1.7 mg of PS80; and f) water comprising, wherein the pH of the composition is from about 4.7 to about 5.5, the container according to claim 15.

20. A kit comprising the pharmaceutical composition according to any one of claims 1 to 14, or the container according to any one of claims 15 to 19, and optionally further comprising instructions for administering the pharmaceutical composition to a subject in need thereof.

21. The pharmaceutical composition according to any one of claims 1 to 14, for use in the treatment of cancer.

22. The pharmaceutical composition is diluted in a container containing 0.9% sodium chloride or D5W to obtain a dosing solution, wherein the container is an IV bag or syringe, the container is inverted to mix the diluted solution, and the container containing the dosing solution is attached to a delivery device, the pharmaceutical composition according to claim 21.

23. The dosing solution maintains the monomer purity of the enobrutinib at about 25 °C for about 6 hours, or at about 2 °C to about 8 °C for about 24 hours, the pharmaceutical composition according to claim 22.

24. The pharmaceutical composition according to any one of claims 21 to 23, formulated for IV infusion over at least about 30 minutes.

25. Diluting the pharmaceutical composition to obtain a body weight-based therapeutic dose of about 6 mg / kg to about 15 mg / kg, the pharmaceutical composition according to any one of claims 21 to 24.

26. Diluting the pharmaceutical composition to obtain a body weight-based therapeutic dose of about 15 mg / kg, the pharmaceutical composition according to any one of claims 21 to 24.

27. The pharmaceutical composition according to any one of claims 21 to 25, wherein the cancer expresses B7-H3.

28. The cancer is: adrenal cancer, AIDS-related cancer, alveolar soft part sarcoma, anal cancer, anal canal squamous cell carcinoma (SCAC), bladder cancer, bone cancer, brain and spinal cord cancer, breast cancer, HER2 ＋ breast cancer, triple-negative breast cancer (TNBC), carotid body tumor, cervical cancer, HPV-related cervical cancer, chondrosarcoma, chordoma, clear cell renal carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, desmoplastic small round cell tumor, epithelioma, endometrial cancer, unselected endometrial cancer, MSI-high endometrial cancer, dMMR endometrial cancer, POLE exonuclease domain mutant positive endometrial cancer, Ewing sarcoma, extraskeletal myxoid chondrosarcoma, gallbladder cancer, bile duct cancer, cholangiocarcinoma, gastric cancer, esophagogastric junction (GEJ) cancer, gestational trophoblastic disease, germ cell tumor, glioblastoma, head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), hematologic malignancy, hepatocellular carcinoma, pancreatic islet cell tumor, Kaposi sarcoma, kidney cancer, leukemia, acute myeloid leukemia, liposarcoma / malignant lipomatous tumor, liver cancer, hepatocellular carcinoma (HCC), lymphoma, diffuse large B-cell lymphoma (DLBCL), non-Hodgkin lymphoma (NHL), lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), medulloblastoma, melanoma, uveal melanoma, meningioma, Merkel cell carcinoma, mesothelioma, mesothelioma of the pharynx, multiple endocrine neoplasia, multiple myeloma, myelodysplastic syndrome, neuroblastoma, neuroendocrine tumor, ovarian cancer, pancreatic cancer, papillary thyroid cancer, parathyroid tumor, pediatric cancer, peripheral nerve sheath tumor, pharyngeal cancer, pheochromocytoma, pituitary tumor, prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), posterior uveal melanoma, renal metastatic cancer, rhabdoid tumor, rhabdomyosarcoma, sarcoma, skin cancer, childhood small round blue cell tumor, neuroblastoma, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, synovial sarcoma, testicular cancer, thymic carcinoma, thymoma, thyroid cancer, urothelial cancer, and uterine cancer, and is selected from the group consisting of, the pharmaceutical composition according to any one of claims 21 to 25.

29. The pharmaceutical composition according to claim 27 or 28, wherein the cancer is anal cancer, bladder cancer, breast cancer, bile duct cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, GEJ cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, prostate cancer, skin cancer, and urothelial cancer.

30. The pharmaceutical composition according to claim 28 or 29, wherein the prostate cancer is mCRPC.