Ox40l antibody formulation

Abstract

Described herein are formulations comprising an antibody that binds OX40L, as well as related methods of treating an inflammatory disorder or disease in a human patient.

Description

[0001] OX40L ANTIBODY FORMULATION

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 723,756 (filed November 22, 2024), the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

[0004] SEQUENCE LISTING

[0005] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on November 21, 2025, is named AOJ-021PC_SL.xml and is 446,419 bytes in size.

[0006] BACKGROUND

[0007] An emerging mechanism in treatments for atopic dermatitis (AD) is targeting 0X40 or OX40L. OX40L is the ligand for 0X40. OX40L is expressed on antigen presenting cells and its interaction with 0X40 causes the accumulation of T cells by providing a survival signal. T cells are important types of white blood cells of the immune system that play a central role in the immune response. OX40L, by playing a role in activating T cells and reprogramming them into inflammatory subsets, contributes to immune overactivation in AD and other inflammatory conditions, such as Systemic Lupus Erythematosus. Additionally, OX40L activation of 0X40 inhibits the expression of FOXP3 and the inhibitory function of regulatory T (Treg) cells. Treg cells can suppress the immune response that leads to worsening symptoms in inflammatory conditions. Therefore, OX40L blockade may lead to clinical benefit in AD and other inflammatory conditions by first suppressing inflammatory T cell activation, and next by increasing the proliferation of Treg cells, which can serve to further reduce inflammatory cells.

[0008] There is a need in the art for improved therapeutics that target OX40L (such as recombinant antibodies), either alone or in combination with additional therapeutic agents, as well as compositions (e.g., formulations) thereof that are stable and suitable for administration to patients. Accordingly, it is an object of the present invention to provide improved compositions for treating patients with inflammatory diseases and conditions. SUMMARY

[0009] Described herein are formulations comprising an antibody that binds OX40L. Also described are vials (e.g., glass vials, polymer vials, syringes (e.g., prefilled syringes), autoinjectors, cartridges, or pens) containing the formulations as well as methods of using the formulations to treat a disease or condition (e.g., an inflammatory disorder or disease) in a subject in need thereof.

[0010] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL; (b) a histidine buffer, an acetate buffer, and / or a succinate buffer; (c) arginine and / or methionine or a salt solution thereof (e.g., a solution of arginine and / or methionine or a salt thereof); and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0.

[0011] In certain aspects, described herein is a formulation consisting of: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL; (b) a histidine buffer, an acetate buffer, and / or a succinate buffer; (c) arginine and / or methionine or a salt solution thereof; and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0.

[0012] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL; (b) a histidine buffer, an acetate buffer, and / or a succinate buffer; (c) arginine and / or methionine or a salt solution thereof; and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0, and wherein the OX40L antibody comprises: a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:368.

[0013] In certain aspects, described herein is a formulation consisting of: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL; (b) a histidine buffer, an acetate buffer, and / or a succinate buffer; (c) arginine and / or methionine or a salt solution thereof; and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0, and wherein the OX40L antibody comprises: a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:368.

[0014] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL; (b) arginine and / or methionine or a salt solution thereof; and (c) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0.

[0015] In certain embodiments, the formulation further comprises ethylenediaminetetraacetic acid (EDTA). In certain embodiments, the formulation further comprises ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA). In certain embodiments, the formulation further comprises about 0.01 mM to about 1 mM EDTA or EGTA (e.g.., about 0.01 mM to about 0.9 mM, about 0.01 mM to about 0.8 mM, about 0.01 mM to about 0.7 mM, about 0.01 mM to about 0.6 mM, about 0.01 mM to about 0.5 mM, about 0.01 mM to about 0.4 mM, about 0.01 mM to about 0.3 mM, about 0.01 mM to about 0.25mM, about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.15 mM, about 0.01 mM to about 0.1 mM, about 0.01 mM to about 0.09 mM, about 0.01 mM to about 0.08 mM, about 0.01 mM to about 0.07 mM, about 0.01 mM to about 0.06 mM, about 0.01 mM to about 0.05 mM, about 0.02 mM to about 1 mM, about 0.03 mM to about 1 mM, about 0.04 mM to about 1 mM, about 0.05 mM to about 1 mM, about 0.06 mM to about 1 mM, about 0.07 mM to about 1 mM, about 0.08 mM to about 1 mM, about 0.09 mM to about 1 mM, about 0.1 mM to about 1 mM, about 0.15 mM to about 1 mM, about 0.2 mM to about 1 mM, about 0.25 mM to about 1 mM, about 0.3 mM to about 1 mM, about 0.4 mM to about 1 mM, about 0.5 mM to about 1 mM, about 0.6 mM to about 1 mM, about 0.7 mM to about 1 mM, about 0.8 mM to about 1 mM, or about 0.9 mM to about 1 mM EDTA or EGTA). In certain embodiments, the formulation further comprises about 0.05 mM EDTA. In certain embodiments, the formulation further comprises about 0.05 mM EGTA.

[0016] In certain embodiments, the formulation further comprises a sugar or sugar alcohol. In certain embodiments, the OX40L antibody is at a concentration between about 125 mg / mL and about 250 mg / mL (e.g., at a concentration of about 130 mg / mL to about 250 mg / mL, about 135 mg / mL to about 245 mg / mL, about 140 mg / mL to about 240 mg / mL, about 145 mg / mL to about 235 mg / mL, about 150 mg / mL to about 230 mg / mL, about 150 mg / mL to about 225 mg / mL, about 150 mg / mL to about 220 mg / mL, about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 150 mg / mL to about 175 mg / mL, about 150 mg / mL to about 170 mg / mL, about 150 mg / mL to about 165 mg / mL, about 150 mg / mL to about 160 mg / mL, about 155 mg / mL to about 200 mg / mL, about 160 mg / mL to about 200 mg / mL, about 165 mg / mL to about 200 mg / mL, about 170 mg / mL to about 200 mg / mL, about 175 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 165 mg / mL to about 220 mg / mL, about 170 mg / mL to about 220 mg / mL, about 175 mg / mL to about 220 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL). In certain embodiments, the OX40L antibody is at a concentration of between about 160 mg / mL and about 220 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of between about 150 mg / mL and about 220 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of between about 150 mg / mL and about 200 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of about 150 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of about 180 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of about 200 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of about 220 mg / mL.

[0017] In certain embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration between about 5 mM and about 20 mM (e.g., at a concentration of about 5 mM to about 19 mM, about 5 mM to about 18 mM, about 5 mM to about 17 mM, about 5 mM to about 16 mM, about 5 mM to about 15 mM, about 5 mM to about 14 mM, about 5 mM to about 13 mM, about 5 mM to about 12 mM, about 5 mM to about 11 mM, about 5 mM to about 10 mM, about 6 mM to about 20 mM, about 7 mM to about 20 mM, about 8 mM to about 20 mM, about 9 mM to about 20 mM, about 10 mM to about 20 mM, about 6 mM to about 14 mM, about 7 mM to about 13 mM, about 8 mM to about 12 mM, about 9 mM to about 11 mM, about 6 mM to about 19 mM, about 7 mM to about 18 mM, about 8 mM to about 17 mM, about 9 mM to about 16 mM, or about 10 mM to about 15 mM, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM). In certain embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 10 mM.

[0018] In certain embodiments, the histidine buffer comprises a histidine and a histidine salt. In certain embodiments, the histidine is L-histidine. In certain embodiments, the histidine salt is L-histidine HC1 monohydrate.

[0019] In certain embodiments, the formulation comprises a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate.

[0020] In certain embodiments, the formulation comprises methionine, and wherein the methionine is L-methionine. In certain embodiments, the L-methionine is at a concentration between about 5 mM and about 20 mM (e.g., at a concentration of about 5 mM to about 19 mM, about 5 mM to about 18 mM, about 5 mM to about 17 mM, about 5 mM to about 16 mM, about 5 mM to about 15 mM, about 5 mM to about 14 mM, about 5 mM to about 13 mM, about 5 mM to about 12 mM, about 5 mM to about 11 mM, about 5 mM to about 10 mM, about 6 mM to about 20 mM, about 7 mM to about 20 mM, about 8 mM to about 20 mM, about 9 mM to about 20 mM, about 10 mM to about 20 mM, about 6 mM to about 14 mM, about 7 mM to about 13 mM, about 8 mM to about 12 mM, about 9 mM to about 11 mM, about 6 mM to about 19 mM, about 7 mM to about 18 mM, about 8 mM to about 17 mM, about 9 mM to about 16 mM, or about 10 mM to about 15 mM, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM). In certain embodiments, the L-methionine is at a concentration of about 10 mM.

[0021] In certain embodiments, the formulation comprises arginine, and wherein the arginine is L-arginine. In certain embodiments, the formulation comprises an L-arginine salt solution. In certain embodiments, the L-arginine salt solution salt solution comprises HC1 monohydrate. In certain embodiments, wherein the L-arginine salt solution is at a concentration between about 40 mM and about 250 mM (e.g., at a concentration of about 50 mM to about 250 mM, about 60 mM to about 250 mM, about 70 mM to about 250 mM, about 80 mM to about 250 mM, about 90 mM to about 250 mM, about 100 mM to about 250 mM, about 110 mM to about 250 mM, about 120 mM to about 250 mM, about 40 mM to about 240 mM, about 40 mM to about 230 mM, about 40 mM to about 220 mM, about 40 mM to about 220 mM, about 40 mM to about 210 mM, about 40 mM to about 200 mM, about 40 mM to about 190 mM, about 40 mM to about 180 mM, about 40 mM to about 170 mM, about 40 mM to about 160 mM, about 40 mM to about 150 mM, about 40 mM to about 140 mM, about 40 mM to about 130 mM, about 40 mM to about 120 mM, about 50 mM to about 200 mM, about 60 mM to about 150 mM, about 70 mM to about 130 mM, about 70 mM to about 125 mM, about 80 mM to about 130 mM, about 90 mM to about 130 mM, about 100 mM to about 130 mM, about 110 mM to about 130 mM, or about 80 mM to about 100 mM, such as 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mM). In certain embodiments, the L-arginine salt solution is at a concentration of about 120 mM.

[0022] In certain embodiments, the formulation comprises L-methionine at a concentration of about 10 mM and L-arginine HC1 at a concentration of about 120 mM.

[0023] In certain embodiments, the formulation further comprises a surfactant. In certain embodiments, the surfactant is a non-ionic surfactant. In certain embodiments, the non-ionic surfactant comprises a polyglycolized glyceride (e.g., a polyethoxylated castor oil, such as polyoxyethylene hydrogenated castor oil 10, 50, or 60); a poloxamer (such as poloxamer 188, poloxamer 181, or poloxamer 407, also known under tradenames Cremophor®, Kolliphor®, Lutrol®, Pluronic®, and Synperonic®); a poloxamine; an alkyl saccharide; an ester saccharide; a polysorbate (such as polysorbate 20, 40, 60, or 80, also known under tradename Tween®), a sorbitan ester or derivative (e.g., a fatty acid ester of sorbitan (also known under tradename Span®)); a polyethylene glycol alkyl ether (also known under tradename Brij®); a fatty acid ester of polyethylene glycol (also known under tradenames Solutol® and Myrj®); an alkyl polyglycoside (e.g., an alkyl polyglucoside (also known under tradenames Triton® and Ecoteric®)); polyoxyl 40 stearate; lauromacrogol 400; glycerol monostearate, sucrose fatty acid ester, methyl cellulose; carboxymethyl cellulose; or a fatty acid monoglyceride (e.g., monolaurin). In certain embodiments, the surfactant is sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetadine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauramidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropylbetaine e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl- or disodium methyl oleyl-taurate; polyethylene glycol (PEG); polypropyl glycol; ethylene glycol; propylene glycol; or a copolymer of ethylene and propylene glycol (e.g., Pluronics, PF68, etc.). In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the surfactant is polysorbate 80. In certain embodiments, the surfactant is a poloxamer. In certain embodiments, the surfactant is poloxamer 188.

[0024] In certain embodiments, the formulation comprises a polysorbate. In certain embodiments the polysorbate is at a concentration between about 0.01% w / v and about 0.15% w / v (e.g., at a concentration of about 0.01% w / v to about 0.14% w / v, about 0.01% w / v to about 0.13% w / v, about 0.01% w / v to about 0.12% w / v, about 0.01% w / v to about 0.11% w / v, about 0.01% w / v to about 0.10% w / v, about 0.01% w / v to about 0.09% w / v, about 0.01% w / v to about 0.08% w / v, about 0.01% w / v to about 0.07% w / v, about 0.01% w / v to about 0.06% w / v, about 0.01% w / v to about 0.05% w / v, about 0.02% w / v to about 0.08% w / v, about 0.03% w / v to about 0.07% w / v, about 0.04% w / v to about 0.06% w / v, about 0.02% w / v to about 0.14% w / v, about 0.03% w / v to about 0.13% w / v, about 0.04% w / v to about 0.12% w / v, or about 0.05% w / v to about 0.11% w / v, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, or 0.15% w / v). In certain embodiments, the polysorbate is at a concentration of about 0.05% w / v. In certain embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In certain embodiments, the polysorbate is polysorbate 80.

[0025] In certain embodiments, the formulation comprises polysorbate 80 at a concentration of about 0.05% w / v.

[0026] In certain embodiments, the formulation comprises a poloxamer. In certain embodiments the poloxamer is at a concentration between about 0.01% w / v and about 0.15% w / v (e.g., at a concentration of about 0.01% w / v to about 0.14% w / v, about 0.01% w / v to about 0.13% w / v, about 0.01% w / v to about 0.12% w / v, about 0.01% w / v to about 0.11% w / v, about 0.01% w / v to about 0.10% w / v, about 0.01% w / v to about 0.09% w / v, about 0.01% w / v to about 0.08% w / v, about 0.01% w / v to about 0.07% w / v, about 0.01% w / v to about 0.06% w / v, about 0.01% w / v to about 0.05% w / v, about 0.02% w / v to about 0.08% w / v, about 0.03% w / v to about 0.07% w / v, about 0.04% w / v to about 0.06% w / v, about 0.02% w / v to about 0.14% w / v, about 0.03% w / v to about 0.13% w / v, about 0.04% w / v to about 0.12% w / v, or about 0.05% w / v to about 0.11% w / v, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, or 0.15% w / v). In certain embodiments the poloxamer is at a concentration between about 0.1 mg / mL and about 1.0 mg / mL (e.g., at a concentration of about 0.1 mg / mL to about 0.9 mg / mL, about 0.1 mg / mL to about 0.8 mg / mL, about 0.1 mg / mL to about 0.7 mg / mL, about 0.1 mg / mL to about 0.6 mg / mL, about 0.1 mg / mL to about 0.5 mg / mL, about 0.2 mg / mL to about 1.0 mg / mL, about 0.3 mg / mL to about 1.0 mg / mL, about 0.4 mg / mL to about 1.0 mg / mL, about 0.5 mg / mL to about 1.0 mg / mL, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / mL). In certain embodiments, the poloxamer is at a concentration of about 0.01% w / v to about 0.05% w / v or about 0.1 mg / mL to about 0.5 mg / mL. In certain embodiments, the poloxamer is at a concentration of about 0.05% w / v or 0.5 mg / mL. In certain embodiments, the poloxamer is poloxamer 188 or poloxamer 407. In certain embodiments, the poloxamer is poloxamer 188.

[0027] In certain embodiments, the pH is between about 5.0 to about 7.0 (e.g., 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8. 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0). In certain embodiments, the pH is between about 5.5 and about 6.5. In certain embodiments, the pH is between about 5.8 and about 6.2. In certain embodiments, the pH is about 6.0.

[0028] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) a histidine buffer (e.g., a histidine buffer comprising L-histidine and L-histidine HC1 monohydrate) at a concentration of about 5 mM to about 20 mM; (c) arginine (e.g., an L-arginine salt solution) at a concentration of about 50 mM to about 200 mM; (d) methionine (e.g., L-methionine) at a concentration of about 5 mM to about 20 mM; and (e) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.01% w / v to about 0.15% w / v, wherein the formulation is at a pH of about 5.5 to about 6.5.

[0029] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) a histidine buffer (e.g., a histidine buffer comprising L-histidine and L-histidine HC1 monohydrate) at a concentration of about 5 mM to about 15 mM (e.g., about 8 to about 12 mM); (c) arginine (e.g., an L-arginine salt solution) at a concentration of about 70 mM to about 130 mM; (d) methionine (e.g., L-methionine) at a concentration of about 5 mM to about 15 mM (e.g., about 8 to about 12 mM); and (e) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v), wherein the formulation is at a pH of about 5.8 to about 6.2.

[0030] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) a histidine buffer (e.g., a histidine buffer comprising L-histidine and L-histidine HC1 monohydrate) at a concentration of about 10 mM to about 15 mM; (c) arginine (e.g., an L-arginine salt solution) at a concentration of about 70 mM to about 130 mM; (d) methionine (e.g., L-methionine) at a concentration of about 10 mM to about 15 mM; and (e) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v), wherein the formulation is at a pH of about 5.8 to about 6.2.

[0031] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05%, wherein the formulation is at a pH of about 6.0.

[0032] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 150 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at pH of about 6.0.

[0033] In certain aspects, described herein is a formulation consisting of: (a) an OX40L antibody at a concentration of about 150 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at pH of about 6.0.

[0034] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 180 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, wherein the formulation is at pH of about 6.0. In certain aspects, described herein is a formulation consisting of: (a) an OX40L antibody at a concentration of about 180 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, wherein the formulation is at pH of about 6.0.

[0035] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration of about 200 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at pH of about 6.0.

[0036] In certain aspects, described herein is a formulation consisting of: (a) an OX40L antibody present at a concentration of about 200 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at pH of about 6.0.

[0037] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration of about 220 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, wherein the formulation is at pH of about 6.0.

[0038] In certain aspects, described herein is a formulation consisting of: (a) an OX40L antibody present at a concentration of about 220 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, wherein the formulation is at pH of about 6.0.

[0039] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) arginine (e.g., an L-arginine salt solution) at a concentration of about 50 mM to about 200 mM; (c) methionine (e.g., L-methionine) at a concentration of about 5 mM to about 20 mM; and (d) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.01% w / v to about 0.15% w / v, wherein the formulation is at a pH of about 5.5 to about 6.5.

[0040] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) arginine (e.g., an L-arginine salt solution) at a concentration of about 70 mM to about 130 mM; (c) methionine (e.g., L-methionine) at a concentration of about 5 mM to about 15 mM (e.g., about 8 to about 12 mM); and (d) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v), wherein the formulation is at a pH of about 5.8 to about 6.2.

[0041] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) arginine (e.g., an L-arginine salt solution) at a concentration of about 70 mM to about 130 mM; (c) methionine (e.g., L-methionine) at a concentration of about 10 mM to about 15 mM; and (d) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v), wherein the formulation is at a pH of about 5.8 to about 6.2.

[0042] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05%, wherein the formulation is at a pH of about 6.0.

[0043] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 150 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05% w / v, at pH of about 6.0.

[0044] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 180 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05% w / v, wherein the formulation is at pH of about 6.0.

[0045] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration of about 200 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05% w / v, at pH of about 6.0. In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration of about 220 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05% w / v, wherein the formulation is at pH of about 6.0.

[0046] In certain embodiments of any of the foregoing aspects, the formulation further comprises EDTA. In certain embodiments, the formulation further comprises EGTA. In certain embodiments, the formulation further comprises about 0.01 mM to about 1 mM EDTA or EGTA (e.g.., about 0.01 mM to about 0.9 mM, about 0.01 mM to about 0.8 mM, about 0.01 mM to about 0.7 mM, about 0.01 mM to about 0.6 mM, about 0.01 mM to about 0.5 mM, about 0.01 mM to about 0.4 mM, about 0.01 mM to about 0.3 mM, about 0.01 mM to about 0.25mM, about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.15 mM, about 0.01 mM to about 0.1 mM, about 0.01 mM to about 0.09 mM, about 0.01 mM to about 0.08 mM, about 0.01 mM to about 0.07 mM, about 0.01 mM to about 0.06 mM, about 0.01 mM to about 0.05 mM, about 0.02 mM to about 1 mM, about 0.03 mM to about 1 mM, about 0.04 mM to about 1 mM, about 0.05 mM to about 1 mM, about 0.06 mM to about 1 mM, about 0.07 mM to about 1 mM, about 0.08 mM to about 1 mM, about 0.09 mM to about 1 mM, about 0.1 mM to about 1 mM, about 0.15 mM to about 1 mM, about 0.2 mM to about 1 mM, about 0.25 mM to about 1 mM, about 0.3 mM to about 1 mM, about 0.4 mM to about 1 mM, about 0.5 mM to about 1 mM, about 0.6 mM to about 1 mM, about 0.7 mM to about 1 mM, about 0.8 mM to about 1 mM, or about 0.9 mM to about 1 mM EDTA or EGTA). In certain embodiments, the formulation further comprises about 0.05 mM EDTA. In certain embodiments, the formulation further comprises about 0.05 mM EGTA.

[0047] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) a histidine buffer (e.g., a histidine buffer comprising L-histidine and L-histidine HC1 monohydrate) at a concentration of about 5 mM to about 15 mM (e.g., about 8 to about 12 mM); (c) arginine (e.g., an L-arginine salt solution) at a concentration of about 70 mM to about 130 mM; (d) methionine (e.g., L-methionine) at a concentration of about 5 mM to about 15 mM (e.g., about 8 to about 12 mM); (e) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v); and (f) about 0.01 mM to about 0.1 mM EDTA, wherein the formulation is at a pH of about 5.8 to about 6.2.

[0048] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; (e) a polysorbate 80 at a concentration of about 0.05%; and (f) about 0.05 mM EDTA, wherein the formulation is at a pH of about 6.0.

[0049] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 150 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; (e) a polysorbate 80 at a concentration of about 0.05% w / v; and (f) about 0.05 mM EDTA, at pH of about 6.0.

[0050] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 180 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; (e) a polysorbate 80 at a concentration of about 0.05% w / v; and (f) about 0.05 mM EDTA, wherein the formulation is at pH of about 6.0.

[0051] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration of about 200 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; (e) a polysorbate 80 at a concentration of about 0.05% w / v; and (f) about 0.05 mM EDTA, at pH of about 6.0.

[0052] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration of about 220 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; (e) a polysorbate 80 at a concentration of about 0.05% w / v; and (f) about 0.05 mM EDTA, wherein the formulation is at pH of about 6.0.

[0053] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) arginine (e.g., an L-arginine salt solution) at a concentration of about 70 mM to about 130 mM; (c) methionine (e.g., L-methionine) at a concentration of about 5 mM to about 15 mM (e.g., about 8 to about 12 mM); (d) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v); and (e) about 0.01 mM to about 0.1 mM EDTA, wherein the formulation is at a pH of about 5.8 to about 6.2.

[0054] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; (d) a polysorbate 80 at a concentration of about 0.05%; and (e) about 0.05 mM EDTA, wherein the formulation is at a pH of about 6.0.

[0055] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 150 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; (d) a polysorbate 80 at a concentration of about 0.05% w / v; and (e) about 0.05 mM EDTA, at pH of about 6.0.

[0056] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody at a concentration of about 180 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; (d) a polysorbate 80 at a concentration of about 0.05% w / v; and (e) about 0.05 mM EDTA, wherein the formulation is at pH of about 6.0.

[0057] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration of about 200 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; (d) a polysorbate 80 at a concentration of about 0.05% w / v; and (e) about 0.05 mM EDTA, at pH of about 6.0.

[0058] In certain aspects, described herein is a formulation comprising: (a) an OX40L antibody present at a concentration of about 220 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; (d) a polysorbate 80 at a concentration of about 0.05% w / v; and (e) about 0.05 mM EDTA, wherein the formulation is at pH of about 6.0.

[0059] In certain embodiments of any of the foregoing aspects, the formulation further comprises a sugar or sugar alcohol. In certain embodiments, the sugar or sugar alcohol is at a concentration between about 1% w / v and about 10% w / v (e.g., at a concentration between 1% w / v and 9% w / v, between 1% w / v and 8% w / v, between 1% w / v and 7% w / v, between 1% w / v and 6% w / v, between 1% w / v and 5% w / v, between 2% w / v and 8% w / v, between 3% w / v and 7% w / v, between 3% w / v and 6% w / v, or about 3% w / v, about 4% w / v, about 5% w / v, or about 6% w / v, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% w / v). In certain embodiments, the sugar or sugar alcohol is at a concentration between about 1% w / v and about 5% w / v (e.g., 1, 2, 3, 4, or 5% w / v). In certain embodiments, the sugar or sugar alcohol is at a concentration between about 3% w / v and about 6% w / v (e.g., 3, 4, 5, or 6% w / v). In certain embodiments, the sugar or sugar alcohol is at a concentration between about 2% w / v and about 4% w / v. In certain embodiments, the sugar or sugar alcohol is at a concentration of about 3% w / v. In certain embodiments, the sugar or sugar alcohol is at a concentration of about 6% w / v. In certain embodiments, the sugar is a monosaccharide (e.g., glucose, xylose, or erythritol), a disaccharide (e.g., sucrose, trehalose, maltose, or galactose), or an oligosaccharide (e.g., stachyose). In certain embodiments, the sugar alcohol is a sugar alcohol derived from a monosaccharide (e.g., mannitol, sorbitol, or xylitol), derived from a disaccharide (e.g., lactitol or maltitol), or derived from an oligosaccharide. In certain embodiments, the sugar or sugar alcohol is a disaccharide. In certain embodiments, the disaccharide is sucrose.

[0060] In certain embodiments, the formulation has a viscosity of about 5-13 cP at 20 °C. In certain embodiments, the formulation is isotonic (e.g., has about the same osmotic pressure as human blood). In certain embodiments, the formulation has an osmolality of 300 ± 50 mOsm / kg.

[0061] In certain embodiments, the formulation is suitable for subcutaneous administration. In certain embodiments, the formulation is suitable for intravenous administration. In certain embodiments, the formulation is sterile.

[0062] In certain embodiments, the anti-OX40L antibody in the formulation remains stable at about 2 °C to 5 °C (e.g., 2, 3, 4, or 5 °C) for at least six months (e.g., at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months), as determined by size exclusion chromatography (e.g., SEC-HPLC or SEC-UPLC). In certain embodiments, the anti-OX40L antibody in the formulation remains stable at about 2 °C to 5 °C (e.g., 2, 3, 4, or 5 °C) for at least one year (e.g., at least 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 years), as determined by size exclusion chromatography (e.g., SEC-HPLC or SEC-UPLC). In certain embodiments, the anti-OX40L antibody in the formulation remains stable at about 2 °C to 5 °C (e.g., 2, 3, 4, or 5 °C) for at least two years, as determined by size exclusion chromatography (e.g., SEC-HPLC or SEC-UPLC). In certain embodiments, the anti-OX40L antibody in the formulation remains stable at about 2 °C to 5 °C (e.g., 2, 3, 4, or 5 °C) for at least three years, as determined by size exclusion chromatography (e.g., SEC-HPLC or SEC-UPLC). In certain embodiments, at least about 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) of the native form of the antibody (i.e., the antibody monomer) is recovered after about six months of storage at about 5° C, as determined by size exclusion chromatography (e.g., SEC-UPLC). In certain embodiments, at least about 95% (e.g., 95%, 96%, 97%, 98%, 99%, or more) of the native form of the antibody (i.e., the antibody monomer) is recovered after about six months of storage at about 5° C, as determined by size exclusion chromatography (e.g., SEC-UPLC). In certain embodiments, at least about 98% of the native form of the antibody (i.e., the antibody monomer) is recovered after about six months of storage at about 5° C, as determined by size exclusion chromatography (e.g., SEC-UPLC).

[0063] In certain embodiments, the OX40L antibody comprises: a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:368.

[0064] In certain embodiments, the OX40L antibody comprises a heavy chain variable region sequence having at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to an amino acid sequence set forth in SEQ ID NO:419.

[0065] In certain embodiments, the OX40L antibody comprises a light chain variable region sequence having at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to an amino acid sequence set forth in SEQ ID NO: 489.

[0066] In certain embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419.

[0067] In certain embodiments, the OX40L antibody comprises a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489.

[0068] In certain embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419 and a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489.

[0069] In certain embodiments, the OX40L antibody is a humanized, human, or chimeric antibody. In certain embodiments, the OX40L antibody is a humanized antibody.

[0070] In certain embodiments, the OX40L antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, the OX40L antibody comprises a human Fc region comprising a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.

[0071] In certain embodiments, the human Fc region comprises a human IgGl Fc region. In certain embodiments, the human Fc region comprises a human IgG4 Fc region. In certain embodiments, the human Fc region comprises a human IgG2 Fc region.

[0072] In certain embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 or SEQ ID NO: 924. In certain embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651. In certain embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 924. A C-terminal lysine is present in SEQ ID NO: 924, which may be cleaved off during manufacture or after administration, resulting in the sequence of SEQ ID NO: 651.

[0073] In certain embodiments, the OX40L antibody comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

[0074] In certain embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738. In certain embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 924 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

[0075] In certain embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 651, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738. In certain embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 924, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738.

[0076] In certain embodiments, the OX40L antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a change in antibody half-life, ADCC activity, ADCP activity, or CDC activity as compared to an otherwise equivalent antibody comprising an Fc region without the one or more amino acid substitutions.

[0077] In certain embodiments, the OX40L antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, and / or CDC activity compared with the Fc region without the one or more amino acid substitutions.

[0078] In certain embodiments, the OX40L antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a decrease in one or more of ADCC activity, ADCP activity, and / or CDC activity compared with the Fc region without the one or more amino acid substitutions.

[0079] In certain embodiments, the OX40L antibody comprises a heavy chain comprising a heavy chain constant domain having a means for extending the half-life of the antibody.

[0080] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP), M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. In certain embodiments, the one or more amino acid substitutions comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS), M252Y / S254T / T256E (YTE), T250Q / M428L, T307A / E380A / N434A, T256D / T307Q (DQ), T256D / T307W (DW), M252Y / T256D (YD), T307Q / Q311V / A378V (QVV), T256D / H285D / T307R / Q311V / A378V (DDRVV), L309D / Q311H / N434S (DHS), S228P / L235E (SPLE), L234A / L235A (LALA), M428L / N434A (LA), L235A / G237A (LAGA), L234A / L235A / G237A (LALAGA), L234A / L235A / P329G (LALAPG), D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS, D265A / LS, LALA / LS, LALAGA / LS, LALAPG / LS, N297A / DHS, D265A / DHS, LALA / DHS, LAGA / DHS, LALAGA / DHS, LALAPG / DHS, SP / YTE, SPLE / YTE, SP / LS, SPLE / LS, SP / DHS, SPLE / DHS, N297A / LA, D265A / LA, LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / N434A, D265A / N434A;, LALA / N434A, LAGA / N434A, LALAGA / N434A, LALAPG / N434A, N297A / N434W, D265A / N434W, LALA / N434W, LAGA / N434W, LALAGA / N434W, LALAPG / N434W, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW, N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, T307Q / Q311V / A378V (QVV), N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV. In some embodiments, the one or more amino acid substitutions is selected from the group consisting of LS, YTE, T250Q / M428L, T307A / E380A / N434A, DQ, DW, YD, QVV, DHS, LA, D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS, D265A / LS, LALA / LS, LALAGA / LS, LALAPG / LS, N297A / DHS, D265A / DHS, LALA / DHS, LAGA / DHS, LALAGA / DHS, LALAPG / DHS, SP / YTE, SPLE / YTE, SP / LS, SPLE / LS, SP / DHS, SPLE / DHS, N297A / LA, D265A / LA, LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW, N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, and LALAPG / QVV.

[0081] Although the EU numbering system is typically used to identify the positions of the various Fc mutations described herein, direct numbering can also be used. For example, in certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 253, 255 and 257, respectively. In certain embodiments, an antibody described herein comprises an Fc region with LALA mutations at positions 235 and 236, respectively. In certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 253, 255 and 257 and with LALA mutations at positions 235 and 236. In certain embodiments, the OX40L antibody described herein comprises the heavy and light chain variable regions of Construct 114 and an Fc region comprising YTE mutations at positions 253, 255 and 257, respectively and with LALA mutations at positions 235 and 236, respectively.

[0082] In certain embodiments the human Fc region comprises a human IgGl Fc region with LALA mutations. In certain embodiments the human Fc region comprises a human IgGl Fc region with YTE mutations. In certain embodiments the human Fc region comprises a human IgGl Fc region with LALA and YTE mutations. In certain embodiments, the human Fc region comprises a human IgGl Fc region with LALA or YTE mutations. In certain embodiments, when direct numbering is used these “YTE” and “LALA” mutations can be located at different amino acid position numbers. In certain embodiments, the LALA mutations are at positions 234 and 235 and the YTE mutations are at positions 252, 254 and 256 (EU numbering). In certain embodiments, the LALA mutations are at positions 235 and 236 (L235A / L236A) and the YTE mutations at positions 253, 255, and 257 (M253Y / S255T / T257E) (direct numbering). In certain embodiments, the OX40L antibody comprises an Fc region, and wherein the Fc region binds to Neonatal Fc receptor (FcRn). In certain embodiments, the Fc region of the antibody binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region. In certain embodiments, the Fc region of the antibody binds to FcRn with a KD of < 1 x 10-7M at pH 6.0.

[0083] In certain embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012. In certain embodiments, the OX40L antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 1010 or SEQ ID NO: 1011. In certain embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012 and a heavy chain comprising the sequence set forth in SEQ ID NO: 1010. The C-terminal lysine in SEQ ID NO: 1010 may not be present if cleavage occurs during manufacture or after administration (which would result in the heavy chain sequence of SEQ ID NO: 1011). In certain embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012 and a heavy chain comprising the sequence set forth in SEQ ID NO: 1011.

[0084] In certain embodiments, the OX40L antibody is a monoclonal antibody.

[0085] In certain embodiments, the OX40L antibody binds an OX40L sequence set forth in SEQ ID NO: 739.

[0086] In certain embodiments, a formulation of the disclosure can be filtrated, such as by Ultrafiltration and Diafiltration (UFDF).

[0087] In certain aspects, described herein is a vial, bag, or bottle comprising the formulation of any one of the aspects and embodiments described herein. In certain embodiments, the vial is a syringe. In certain embodiments, the vial is a prefilled syringe. In certain embodiments, the vial is an autoinjector. In certain embodiments, the vial is a pen. In certain embodiments, the vial is a glass vial. In certain embodiments, the vial is a polymer vial. In certain embodiments, the vial is a cartridge (e.g., an autoinjector cartridge, such as a prefilled autoinjector cartridge).

[0088] In certain embodiments, an extractable volume of the vial is between about 1.0 mL and about 5.0 mL (e.g., about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mL). In certain embodiments, an extractable volume of the vial is between about 1.0 mL and about 3.0 mL (e.g., 1.0, 1.5, 2.0, 2.5, or 3.0 mL). In certain embodiments, the extractable volume of the vial is about 2.0 mL. In certain aspects, described herein is a composition comprising the formulation or vial of any one of the aspects and embodiments described herein for use in the treatment of an inflammatory disorder or disease.

[0089] In certain embodiments, the formulation or vial of any one of the aspects and embodiments described herein is for use in the treatment of atopic dermatitis. In certain embodiments, the treatment reduces disease severity in a subject, wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

[0090] In certain embodiments, the formulation or vial of any one of the aspects and embodiments described herein is for use in the treatment of an inflammatory disorder or disease selected from the group consisting of asthma; idiopathic pulmonary fibrosis; alopecia areata; chronic sinusitis with nasal polyps; (e.g., Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)); Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA); Prurigo Nodularis (PN); Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO); Bullous Pemphigoid (BP); Cold Inducible Urticaria (ColdU); Allergic Fungal Rhinosinusitis (AFRS); Allergic Bronchopulmonary Aspergillosis (ABPA); Chronic Obstructive Pulmonary Disease (COPD); an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis; lupus; rheumatoid arthritis (RA); psoriasis; hidradenitis suppurativa; celiac disease; systemic sclerosis; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; and nephrogenic systemic fibrosis.

[0091] In certain aspects, described herein is a therapeutic kit comprising: (i) a dose of any one of the formulations described herein (e.g., any one of the formulations described herein in unit dosage form) and (ii) a means for delivery of the formulation to a human. In certain embodiments, the means is a syringe (e.g., a pre-filled syringe). In certain embodiments, the means is an autoinjector. In certain embodiments, the means is an on-body device (e.g., an on-body injector). In certain embodiments, the therapeutic kit is for use in treating an inflammatory disorder or disease in a human patient.

[0092] In certain aspects, described herein is a kit comprising a vial (e.g., a syringe, such as a pre-filled syringe, an autoinjector, a cartridge, such as an autoinjector cartridge, a glass vial, or a polymer vial) and instructions for use (e.g., for treating a subject having an inflammatory disorder or disease). In certain aspects, described herein is a method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation of any one of the aspects and embodiments described herein. In certain embodiments, the formulation is administered using a vial described herein (e.g., a prefilled syringe or autoinjector).

[0093] In certain embodiments, the inflammatory disorder or disease is atopic dermatitis. In certain embodiments, the inflammatory disorder or disease is asthma; idiopathic pulmonary fibrosis; alopecia areata; chronic sinusitis with nasal polyps; (e.g., Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)); Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA); Prurigo Nodularis (PN); Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO); Bullous Pemphigoid (BP); Cold Inducible Urticaria (ColdU); Allergic Fungal Rhinosinusitis (AFRS); Allergic Bronchopulmonary Aspergillosis (ABPA); Chronic Obstructive Pulmonary Disease (COPD); an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis; lupus; rheumatoid arthritis (RA); psoriasis; hidradenitis suppurativa; celiac disease; systemic sclerosis; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

[0094] In certain aspects, described herein is a method for treating a pathology associated with elevated levels of OX40L in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation of any one of the aspects and embodiments described herein. In certain embodiments, the formulation is administered using a vial described herein (e.g., a prefilled syringe or autoinjector).

[0095] In certain aspects, described herein is a method of manufacturing an intermediate preparation of an OX40L antibody comprising: (a) obtaining a purified preparation of the OX40L antibody; and (b) adjusting the matrix of the purified preparation of step (a), wherein adjusting the matrix comprises performing Ultrafiltration and Diafiltration (UFDF) with a diafiltration buffer comprising a histidine buffer and arginine or a salt solution thereof, wherein the diafiltration buffer is at a pH of from about 5.4 to about 7.0 (e.g., about 5.4 to about 6.0), thereby obtaining the intermediate preparation of the OX40L antibody. In certain embodiments, the intermediate preparation of the OX40L antibody has a higher concentration of the OX40L antibody relative to the purified preparation.

[0096] In certain embodiments, the method of manufacturing further comprises: (c) formulating the intermediate preparation to obtain a formulation of the OX40L antibody. In certain embodiments, the formulation of the OX40L antibody comprises the formulation of any one of the aspects or embodiments described herein.

[0097] In certain embodiments, the histidine buffer is at a concentration between about 5 mM and about 20 mM (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM). In certain embodiments, the histidine buffer is at a concentration of about 10 mM. In certain embodiments, the histidine buffer comprises a histidine and a histidine salt. In certain embodiments, the histidine is L-histidine. In certain embodiments, the histidine salt is L-histidine HC1 monohydrate. In certain embodiments, the arginine is L-arginine. In certain embodiments, the arginine is an L-arginine salt solution. In certain embodiments, the L-arginine salt solution salt solution comprises HC1 monohydrate. In certain embodiments, the L-arginine salt solution is at a concentration between about 40 mM and about 150 mM (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mM). In certain embodiments, the L-arginine salt solution is at a concentration of about 120 mM.

[0098] DETAILED DESCRIPTION

[0099] Definitions

[0100] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0101] As used herein, the singular forms “a,” “an,” and “the” include plural references unless indicated otherwise.

[0102] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.

[0103] For all compositions described herein, and all methods using a composition described herein, the compositions can either comprise the listed components or steps, or can “consist essentially of’ the listed components or steps. When a composition is described as “consisting essentially of’ the listed components, the composition contains the components listed, and may contain other components which do not substantially affect the condition being treated, but do not contain any other components which substantially affect the condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the condition being treated, the composition does not contain a sufficient concentration or amount of the extra components to substantially affect the condition being treated. When a method is described as “consisting essentially of’ the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed. As a non-limiting specific example, when a composition is described as “consisting essentially of’ a component, the composition may additionally contain any amount of pharmaceutically acceptable carriers, vehicles, or diluents and other such components which do not substantially affect the condition being treated.

[0104] An “effective amount” or “therapeutically effective amount” as used herein refers to an amount of therapeutic compound, such as an OX40L antibody, administered to an individual, either as a single dose or as part of a series of doses, which is effective to produce or contribute to a desired therapeutic effect, either alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect include reducing an aberrant immune response, slowing or delaying disease development; stabilization of disease; and amelioration of one or more symptoms. An effective amount may be given in one or more dosages.

[0105] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0106] The term “sufficient amount” means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate an immune response in a subject.

[0107] As used herein, the terms “subject,” “patient,” and “individual” are used interchangeably herein. The term “subject,” “patient,” or “individual” means a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In certain embodiments, the subject is a human. In certain embodiments the subject has a disease or condition that can be treated with an antibody provided herein.

[0108] The terms “formulation,” “pharmaceutical formulation,” and “pharmaceutical composition” refer to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective in treating a subject, and which contains no additional components which are unacceptably toxic to the subject in the amounts provided in the formulation.

[0109] As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit / risk ratio. Preferably, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[0110] The terms “modulate” and “modulation” refer to reducing or inhibiting or, alternatively, activating or increasing, a recited variable. The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0111] The terms “reduce” and “inhibit” refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or greater in a recited variable.

[0112] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, where applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0113] For any of the structural and functional characteristics described herein, methods of determining these characteristics are known in the art.

[0114] The term “optionally” is meant, when used sequentially, to include from one to all of the enumerated combinations and contemplates all sub-combinations.

[0115] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C), glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G), histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V). As used herein, an amino acid described herein may refer to its L-isomer form. For example, methionine may refer to L-methionine, proline may refer to L-proline, and arginine may refer to L-arginine.

[0116] The term “affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen or epitope).

[0117] The term “kd” (sec-1), as used herein, refers to the dissociation rate constant of a particular antibody - antigen interaction. This value is also referred to as the koff value. The term “ka” (M-lxsec-1), as used herein, refers to the association rate constant of a particular antibody -antigen interaction. This value is also referred to as the kon value.

[0118] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody -antigen interaction. KD = kd / ka. In certain embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0119] The term “KA” (M-l), as used herein, refers to the association equilibrium constant of a particular antibody-antigen interaction. KA = ka / kd.

[0120] As used herein, “administration” refers to providing or giving a subject a therapeutic agent (e.g., an OX40L antibody described herein) by any effective route. Exemplary routes of administration are described herein below.

[0121] As used herein, the term “polypeptide” describes a single polymer in which the monomers are amino acid residues which are covalently conjugated together through amide bonds. A polypeptide is intended to encompass any amino acid sequence, either naturally occurring, recombinant, or synthetically produced.

[0122] As used herein, the terms “conservative mutation,” “conservative substitution,” and “conservative amino acid substitution” refer to a substitution of one or more amino acids for one or more different amino acids that exhibit similar physicochemical properties, such as polarity, electrostatic charge, and steric volume. These properties are summarized for each of the twenty naturally occurring amino acids in Table 1 below.

[0123] Table 1. Representative physicochemical properties of naturally occurring amino acids Amino Acid 3 Letter 1 Letter Side-chain Electrostatic Steric Code Code Polarity character at Volume† physiological pH

[0124] (7.4)

[0125] Alanine Ala A nonpolar neutral small Arginine Arg R polar cationic large Asparagine Asn N polar neutral intermediate Aspartic acid Asp D polar anionic intermediate Cysteine Cys C nonpolar neutral intermediate Glutamic acid Glu E polar anionic intermediate Glutamine Gin Q polar neutral intermediate Glycine Gly G nonpolar neutral small Histidine His H polar Both neutral and large cationic forms in

[0126]

[0127] Amino Acid 3 Letter 1 Letter Side-chain Electrostatic Steric Code Code Polarity character at Volume1physiological pH

[0128] (7.4)

[0129] equilibrium at pH

[0130] 7.4

[0131] Isoleucine Ile I nonpolar neutral large Leucine Leu L nonpolar neutral large Lysine Lys K polar cationic large Methionine Met M nonpolar neutral large Phenylalanine Phe F nonpolar neutral large Proline Pro P nonpolar neutral intermediate Serine Ser S polar neutral small Threonine Thr T polar neutral intermediate Tryptophan Trp W nonpolar neutral bulky Tyrosine Tyr Y polar neutral large Valine Val V nonpolar neutral intermediate †based on volume in cubic angstroms: 50-100 is small, 100-150 is intermediate, 150-200 is large, and >200 is bulky

[0132]

[0133] From this table it is appreciated that the conservative amino acid families include (i) G, A, V, L and I; (ii) D and E; (iii) C, S and T; (iv) H, K and R; (v) N and Q; and (vi) F, Y and W. A conservative mutation or substitution is therefore one that substitutes one amino acid for a member of the same amino acid family (e.g., a substitution of Ser for Thr or Lys for Arg).

[0134] The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies.

[0135] A “anti-OX40L antibody,” “OX40L antibody,” or “OX40L specific antibody” is an antibody, as provided herein, which specifically binds to the antigen OX40L.

[0136] The term “epitope” means a portion of an antigen that specifically binds to an antibody. The term “hypervariable region” or “HVR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops (“hypervariable loops”).

[0137] The term “antigen-binding domain” means the portion of an antibody that is capable of specifically binding to an antigen or epitope.

[0138] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0139] The term “human antibody” refers to an antibody which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0140] The term “humanized antibody” refers to a protein having a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that the humanized antibody is less likely to induce an immune response, and / or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject.

[0141] The term “multispecific antibody” refers to an antibody that comprises two or more different antigen-binding domains that collectively specifically bind two or more different epitopes.

[0142] A “monospecific antibody” is an antibody that comprises one or more binding sites that specifically bind to a single epitope. An example of a monospecific antibody is a naturally occurring IgG molecule which, while divalent (i.e., having two antigen-binding domains), recognizes the same epitope at each of the two antigen-binding domains. The binding specificity may be present in any suitable valency.

[0143] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0144] The term “single-chain” refers to a molecule comprising amino acid monomers linearly linked by peptide bonds. In a particular such embodiment, the C-terminus of the Fab light chain is connected to the N-terminus of the Fab heavy chain in the single-chain Fab molecule. As described in more detail herein, an scFv has a variable domain of light chain (VL) connected from its C-terminus to the N-terminal end of a variable domain of heavy chain (VH) by a polypeptide chain. Alternately the scFv comprises of polypeptide chain where in the C-terminal end of the VH is connected to the N-terminal end of VL by a polypeptide chain.

[0145] The “Fab fragment” (also referred to as fragment antigen-binding) contains the constant domain (CL) of the light chain and the first constant domain (CHI) of the heavy chain along with the variable domains VL and VH on the light and heavy chains respectively. The variable domains comprise the complementarity determining loops (CDR, also referred to as hypervariable region) that are involved in antigen-binding. Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region.

[0146] “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with B-mercaptoethanol.

[0147] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0148] “Single-chain Fv” or “sFv” or “scFv” includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. In one embodiment, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding. For a review of scFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 11, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315 (1994).

[0149] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminal of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv i.e., VH-VL or VL- VH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG4 Fc domain.

[0150] The term “single domain antibody” or “sdAb” refers to a molecule in which one variable domain of an antibody specifically binds to an antigen without the presence of the other variable domain. Single domain antibodies, and fragments thereof, are described in Arabi Ghahroudi et al., FEBS Letters, 1998, 414:521-526 and Muyldermans et al., Trends in Biochem. Sci., 2001, 26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies. SdAbs are fairly stable and easy to express as fusion partner with the Fc chain of an antibody (Harmsen MM, De Haard HJ (2007). “Properties, production, and applications of camelid single-domain antibody fragments,” Appl. Microbiol Biotechnol. 77(1): 13-22).

[0151] The terms “full length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having heavy chains that comprise an Fc region. For example, when used to refer to an IgG molecule, a “full length antibody” is an antibody that comprises two heavy chains and two light chains.

[0152] The term “antibody fragment” refers to an antibody that comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0153] The term “Fc domain” or “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions.

[0154] The term “purified” or “substantially purified” refers to a construct described herein, or variant thereof that may be substantially or essentially free of components that normally accompany or interact with the protein as found in its naturally occurring environment, i.e., a native cell, or host cell in the case of recombinantly produced antibody that in certain embodiments, is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight or by relative concentration) of contaminating protein.

[0155] The term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., using publicly available computer software such as BLAST, BLASTP, BLASTN, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software or other algorithms available to persons of skill) or by visual inspection. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.

[0156] For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0157] Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0158] Ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50.

[0159] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0160] The term “stable formulation” refers to a formulation in which the protein of interest (here an antibody or an antigen binding fragment thereof) essentially retains its physical, chemical, and / or biological properties upon storage. In order to measure the protein stability in a formulation, various analytical methods are well within the knowledge of the skilled person (see some examples in the Example section). Stability is typically assessed at a selected temperature (for instance -70 °C, -40 °C, -20° C, 2-8 °C, 25 °C, 35 °C, or more) for a selected time period (e.g., 3 months, 6 months, 12 months, or more). As an antibody, once formulated, it may be stored frozen (-20 °C to -70 °C), under refrigerated conditions (typically 2-8 °C), or at room temperature (typically 20-26 °C) before being prepared for administration to a patient. It is important that the formulated antibody is stable over time at least at 2-25 °C or under frozen conditions (-20 to -70 °C), as shown for example at 2-8 °C, 25 °C, -20 °C, -40 °C, and -70 °C. Various values can be used to conclude about stability over a given time period (in comparison of the initial data), such as (and not limited to): 1) no more than 10% of alteration of the monomeric form of the antibody, 2) no more than 10% of increase in High Molecular Weight Species (HMW; also herein referred to as aggregates), 3) no more than 10% of increase in Low Molecular Weight species (LMW), 4) no more than +1-0.3 unit variation of the pH, 5) changes in charge variation, 6) changes in potency, or 7) changes in particulates, the relevant changed ranges of which one of skill in the art could determine.

[0161] In all the embodiments of the invention, “formulation,” “pharmaceutical formulation,” and “pharmaceutical composition” can also be referred to as “stable formulation” without any differentiation.

[0162] As used herein, the term “vial” refers to a container that holds the drug product. In some embodiments, the vial may be a vial, a pen, an autoinjector, a cartridge, or a syringe. In some embodiments, the vial may be a vial, e.g., a glass vial, a syringe, such as a pre-filled syringe, or a pre-filled autoinjector, e.g., an autoinjector cartridge.

[0163] The term "atopic dermatitis disease severity outcome measure" refers to a determination of certain signs, symptoms, features or parameters that have been associated with atopic dermatitis and that can be quantitatively or qualitatively assessed. Exemplary atopic dermatitis disease severity outcome measures include " Eczema Area and Severity Index" (EASI), " Severity Scoring of Atopic Dermatitis" (SCORAD), " Validated Investigator Global Assessment-Atopic Dermatitis" (vIGA-AD), " Investigator Global Assessment of Signs" (IGSA), Rajka / Langeland Atopic Dermatitis Severity Score, “Body Surface Area” (BSA), and Patient-Reported Outcomes including Pruritus Visual Analog Scale (an aspect of disease severity assessed as part of SCORAD), Sleep Loss Visual Analog Scale (an aspect of disease severity assessed as part of SCORAD), Atopic Dermatitis Symptom Diary (ADSD), Atopic Dermatitis Impact Questionnaire (ADIQ), Dermatology Life Quality Index (DLQI) (Finlay and Khan, Clin Exper Dermatol 1994;19:210), 5-D Itch Scale (Elman et al., Br J Dermatol 2010;162(3):587-593), Itch Numeric Rating Scale (I-NRS) (see Naegeli eta / ., International Journal of Dermatology. 2015;54(6):715-722; and Newton L, et al., J. Patient Rep. Outcomes. 2019;3(l):42), and the Patient-Oriented Eczema Measure (POEM) (www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx).

[0164] Antibody Structure

[0165] The present application provides antibodies and formulations comprising an OX40L antibody.

[0166] The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. The “class” of an antibody or immunoglobulin refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 8, E, y, and p, respectively.

[0167] An exemplary immunoglobulin (antibody) structural unit is composed of two pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminal domain of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable fight chain (VL) and variable heavy chain (VH) refer to these light and heavy chain domains respectively. The IgGl heavy chain comprises of the VH, CHI, CH2, and CH3 domains respectively from the N- to C-terminus. The light chain comprises of the VL and CL domains from N- to C-terminus. The IgGl heavy chain comprises a hinge between the CHI and CH2 domains. In certain embodiments, the immunoglobulin constructs comprise at least one immunoglobulin domain from IgG, IgM, IgA, IgD, or IgE connected to a therapeutic polypeptide. In some embodiments, the immunoglobulin domain found in an antibody provided herein, is from or derived from an immunoglobulin-based construct such as a diabody or a nanobody. In certain embodiments, the immunoglobulin constructs described herein comprise at least one immunoglobulin domain from a heavy chain antibody such as a camelid antibody. In certain embodiments, the immunoglobulin constructs provided herein comprise at least one immunoglobulin domain from a mammalian antibody such as a bovine antibody, a human antibody, a camelid antibody, a mouse antibody, or any chimeric antibody.

[0168] In some embodiments, the antibodies provided herein comprise a heavy chain. In one embodiment, the heavy chain is an IgA. In one embodiment, the heavy chain is an IgD. In one embodiment, the heavy chain is an IgE. In one embodiment, the heavy chain is an IgG. In one embodiment, the heavy chain is an IgM. In one embodiment, the heavy chain is an IgGl. In one embodiment, the heavy chain is an IgG2. In one embodiment, the heavy chain is an IgG3. In one embodiment, the heavy chain is an IgG4. In one embodiment, the heavy chain is an IgAl. In one embodiment, the heavy chain is an IgA2.

[0169] In some embodiments, an antibody is an IgGl antibody. In some embodiments, an antibody is an IgG3 antibody. In some embodiments, an antibody is an IgG2 antibody. In some embodiments, an antibody is an IgG4 antibody.

[0170] Generally, native four-chain antibodies comprise six hypervariable regions (HVRs); three in the VH (Hl, H2, and H3), and three in the VL (LI, L2, and L3). HVRs generally comprise amino acid residues from the hypervariable loops and / or from the complementarity determining regions (CDRs), the latter being of highest sequence variability and / or involved in antigen recognition. With the exception of CDR1 in VH, CDRs generally comprise the amino acid residues that form the hypervariable loops. HVRs are also referred to as CDRs, and these terms are used herein interchangeably in reference to portions of the variable region that form the antigen-binding regions. This particular region has been described by Kabat et al., U. S. Dept, of Health and Human Services, Sequences of Proteins of Immunological Interest (1983) and by Chothia et al., J Mol Biol 196:901-917 (1987), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The exact residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.

[0171] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732-745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Pliickthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme); each of which is incorporated by reference in its entirety.

[0172] Table 2 provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes.

[0173] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.

[0174] Table 2. Residues in CDRs According to Kabat and Chothia Numbering Schemes CDR Kabat Chothia

[0175] LI L24-L34 L24-L34

[0176] L2 L50-L56 L50-L56

[0177] L3 L89-L97 L89-L97

[0178] Hl (Kabat Numbering) H31-H35B H26-H32 or H34*

[0179] Hl (Chothia Numbering) H31-H35 H26-H32

[0180] H2 H50-H65 H52-H56

[0181] H3 H95-H102 H95-H102

[0182]

[0183] * The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR.

[0184] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0185] One example of an antigen-binding domain is an antigen-binding domain formed by a VH-VL dimer of an antibody. Another example of an antigen-binding domain is an antigenbinding domain formed by diversification of certain loops from the tenth fibronectin type III domain of an Adnectin. An antigen-binding domain can include CDRs 1, 2, and 3 from a heavy chain in that order; and CDRs 1, 2, and 3 from a light chain in that order.

[0186] Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter may be lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination such as, for example, testing for antibody binding to OX40L variants with different point-mutations or to chimeric OX40L variants.

[0187] To screen for antibodies which bind to an epitope on a target antigen bound by an antibody of interest (e.g., OX40L), a routine cross-blocking assay such as that described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988), can be performed. Alternatively, or additionally, epitope mapping can be performed by methods known in the art.

[0188] Chimeric antibodies are antibodies in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0189] Human antibodies are antibodies which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0190] A humanized antibody has a sequence that differs from the sequence of an antibody derived from a non-human species by one or more amino acid substitutions, deletions, and / or additions, such that the humanized antibody is less likely to induce an immune response, and / or induces a less severe immune response, as compared to the non-human species antibody, when it is administered to a human subject. In one embodiment, certain amino acids in the framework and constant domains of the heavy and / or light chains of the non-human species antibody are mutated to produce the humanized antibody. In another embodiment, the constant domain(s) from a human antibody are fused to the variable domain(s) of a non-human species. In another embodiment, one or more amino acid residues in one or more CDR sequences of a non-human antibody are changed to reduce the likely immunogenicity of the non-human antibody when it is administered to a human subject, wherein the changed amino acid residues either are not critical for immunospecific binding of the antibody to its antigen, or the changes to the amino acid sequence that are made are conservative changes, such that the binding of the humanized antibody to the antigen is not significantly worse than the binding of the non-human antibody to the antigen. Examples of how to make humanized antibodies can be found in U. S. Pat. Nos. 6,054,297, 5,886,152 and 5,877,293. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323-329; andPresta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0191] In some embodiments, an antibody can bind to two or more different epitopes. The two or more different epitopes may be epitopes on the same antigen (e.g., a single OX40L) or on different antigens (e.g., different OX40L molecules, or an OX40L molecule and a non-OX40L molecule). In some embodiments, a multi-specific antibody binds two different epitopes (i.e., a “bispecific antibody”). In some embodiments, a multi-specific antibody binds three different epitopes (i.e., a “trispecific antibody”).

[0192] Anti-OX40L antibodies can include those described herein. In some embodiments, the antibody comprises an alternative scaffold. In some embodiments, the antibody consists of an alternative scaffold. In some embodiments, the antibody consists essentially of an alternative scaffold. In some embodiments, the antibody comprises an antibody fragment. In some embodiments, the antibody consists of an antibody fragment. In some embodiments, the antibody consists essentially of an antibody fragment.

[0193] In some embodiments the antibodies are monoclonal antibodies.

[0194] In some embodiments the antibodies are polyclonal antibodies.

[0195] In some embodiments the antibodies are produced by hybridomas. In other embodiments, the antibodies are produced by recombinant cells engineered to express the desired variable and constant domains.

[0196] In some embodiments the antibodies may be single chain antibodies or other antibody derivatives retaining the antigen specificity and the lower hinge region or a variant thereof.

[0197] In some embodiments the antibodies may be polyfunctional antibodies, recombinant antibodies, human antibodies, humanized antibodies, fragments or variants thereof. In particular embodiments, the antibody fragment or a derivative thereof is selected from a Fab fragment, a Fab'2 fragment, a CDR, and ScFv.

[0198] In some embodiments, the antibodies are capable of forming an immune complex. For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).

[0199] One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov / ).

[0200] OX40L Antibodies

[0201] In some embodiments, the present disclosure provides formulations comprising: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL (e.g., at a concentration of about 130 mg / mL to about 250 mg / mL, about 135 mg / mL to about 245 mg / mL, about 140 mg / mL to about 240 mg / mL, about 145 mg / mL to about 235 mg / mL, about 150 mg / mL to about 230 mg / mL, about 150 mg / mL to about 225 mg / mL, about 150 mg / mL to about 220 mg / mL, about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 150 mg / mL to about 175 mg / mL, about 150 mg / mL to about 170 mg / mL, about 150 mg / mL to about 165 mg / mL, about 150 mg / mL to about 160 mg / mL, about 155 mg / mL to about 200 mg / mL, about 160 mg / mL to about 200 mg / mL, about 165 mg / mL to about 200 mg / mL, about 170 mg / mL to about 200 mg / mL, about 175 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 165 mg / mL to about 220 mg / mL, about 170 mg / mL to about 220 mg / mL, about 175 mg / mL to about 220 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL); (b) a histidine buffer, an acetate buffer, and / or a succinate buffer; (c) arginine and / or methionine or a salt solution thereof (e.g., a solution of arginine and / or methionine or a salt thereof); and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to 7.0.

[0202] In some embodiments, the present disclosure provides formulations comprising: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL (b) arginine and / or methionine or a salt solution thereof (e.g., a solution of arginine and / or methionine or a salt thereof); and (c) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to 7.0.

[0203] In some embodiments, the OX40L antibody comprises: a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:368.

[0204] In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence having at least 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence set forth in SEQ ID NO:419.

[0205] In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419.

[0206] In some embodiments, the OX40L antibody comprises a light chain variable region sequence having at least 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence set forth in SEQ ID NO: 489.

[0207] In some embodiments, the OX40L antibody comprises a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489.

[0208] In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419 with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the OX40L antibody comprises a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489 with up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as “variants.” In some embodiments, such variants are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0209] In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419 and a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489.

[0210] In some embodiments, the OX40L antibody comprises Construct 114. In some embodiments, the OX40L antibody comprises the CDR and / or variable region sequences set forth in Table 3.

[0211] Table 3. Sequences of OX40L Antibody Construct - VH, VL, and Associated CDRs Identifier VH and Heavy chain CDRs VL and Light chain CDRs 114 VH (SEQ ID NO:419) VL (SEQ ID NO:489)

[0212] CDR1: Kabat (SEQ ID NO:1) CDR1: Kabat (SEQ ID NO:258) Chothia (SEQ ID NO:22) Chothia (SEQ ID NO:286) IMGT (SEQ ID NO:44) IMGT (SEQ ID NO:311) CDR2: Kabat (SEQ ID NO:70) CDR2: Kabat (SEQ ID NO:335) Chothia (SEQ ID NO: 111) Chothia (amino acid sequence ASS) IMGT (SEQ ID NO: 142) IMGT (amino acid sequence ASS) CDR3: Kabat (SEQ ID NO: 175) CDR3: Kabat (SEQ ID NO:368) Chothia (SEQ ID NO:203) Chothia (SEQ ID NO: 394) IMGT (SEQ ID NO:223) IMGT (SEQ ID NO:368)

[0213]

[0214] In some embodiments, the OX40L antibody comprises 1, 2, 3, 4, 5, or 6 of the CDRs of Table 3 or Table 4. In some embodiments, the OX40L antibody comprises 6 of the Kabat CDRs of Table 3 or Table 4 or the Chothia CDRs of Table 3 or Table 4 or the IMGT CDRs of Table 3 or Table 4. Table 4. Consensus Sequences of Construct 114

[0215] Variants of 114

[0216] CDRH1 (Kabat) X1X2AMX3, where Xi = N, S, T, or I,

[0217] X2= Y or H, and X3= T, Y, or S

[0218] CDRH2 (Kabat) LIX1GX2GX3X4TX5YADSVX6G, 552 where Xi = S or T, X2 = S or G, X3= G, A, or S, X4 = L, S, I, or

[0219] V, X5= K, H, N, or Y, and X6= K or R

[0220] CDRH3 (Kabat) X1EGLTX2GEX3, where Xi = D or E, 553

[0221] X2= T or S, and X3= Y, F, or S

[0222] CDRL1 (Kabat) RX1SQX2IRNX3LX4, where Xi = A or 554

[0223] T, X2= D, G, or A, X3= D or N, and X4 = A, G, or D

[0224] CDRL2 (Kabat) X1X2SX3X4X5S, where Xi = A or V,

[0225] X2= S, V, T, or A, X3= S or N, X4= Lor F, and X5= Q or K

[0226] CDRL3 (Kabat) LQHX1X2YPFX3, where Xi = N or S, 556

[0227] X2= N, S, or T, and X3= T or S

[0228] CDRH1 (Chothia) GFTFX1X2X3, where Xi = S, R, N, 557

[0229] G, or T, X2= N, S, T, or I, and X3= Y or H

[0230] CDRH2 (Chothia) X1GX2GX3X4, where Xi = S or T, X2

[0231] = S or G, X3 = G, A, or S, and X4 = L, S, I, or V

[0232] CDRH3 (Chothia) EGLTXiGE, where Xi = T or S 559 CDRL1 (Chothia) SQX1IRNX2, where Xi = D, G, or A, 560

[0233] and X2 = D or N

[0234] CDRL2 (Chothia) X1X2S, where Xi = A or V, and X2=

[0235] S, V, T, or A

[0236] CDRL3 (Chothia) HX1X2YPF, where Xi = N or S, and 562

[0237] X2= N, S, or T

[0238] CDRH1 (IMGT) GFTFX1X2X3A, where Xi = S, R, N, 563

[0239] G, or T, X2= N, S, T, or I, andX3= Y or H

[0240] CDRH2 (IMGT) IX1GX2GX3X4T, where Xi = S or T, 564

[0241] X2= S or G, X3= G, A, or S, and X4 = L, S, I, or V

[0242] CDRH3 (IMGT) X1KX2EGLTX3GEX4, where Xi = V 565

[0243] or A, X2 = D or E, X3 = T or S, and X4 = Y, F, or S

[0244] CDRL1 (IMGT) QX1IRNX2, where Xi = D, G, or A, 566

[0245] and X2 = D or N

[0246] CDRL2 (IMGT) X1X2S, where Xi = A or V, and X2=

[0247] S, V, T, or A

[0248] CDRL3 (IMGT) LQHX1X2YPFX3, where Xi = N or S, 568

[0249]

[0250] X2= N, S, or T, and X3= T or S

[0251] In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence selected from an amino acid sequence set forth in any one of SEQ ID NOs: 637-737 and 910-1009, or an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence having at least 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence set forth in SEQ ID NO: 651. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence having at least 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence set forth in SEQ ID NO: 924.

[0252] In some embodiments, the OX40L antibody comprises a constant heavy chain sequence set forth in SEQ ID NO: 651. In some embodiments, the OX40L antibody comprises a constant heavy chain sequence set forth in SEQ ID NO: 924.

[0253] In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence having at least 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence set forth in SEQ ID NO: 738.

[0254] In some embodiments, the OX40L antibody comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

[0255] In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 924 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

[0256] In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 651, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 924, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738.

[0257] Although the OX40L antibody may be produced using a polynucleotide sequence that encodes a constant heavy chain region containing a C-terminal lysine {e.g., a polynucleotide sequence encoding SEQ ID NO: 924), the C-terminal lysine may be cleaved off during manufacture or after administration (resulting in, e.g., an antibody containing a constant heavy chain sequence of SEQ ID NO: 651). Accordingly, the OX40L antibody that is contained in a formulation described herein for administration to a subject can have the constant heavy chain sequence of SEQ ID NO: 924, SEQ ID NO: 651, or a mixture thereof.

[0258] In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012. In some embodiments, the OX40L antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 1010 or SEQ ID NO: 1011. In some embodiments, the OX40L antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 1010. In some embodiments, the OX40L antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 1011.

[0259] In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012 and a heavy chain comprising the sequence set forth in SEQ ID NO: 1010. The C-terminal lysine in SEQ ID NO: 1010 may not be present if cleavage occurs during manufacture or after administration (which would result in the heavy chain sequence of SEQ ID NO: 1011). In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012 and a heavy chain comprising the sequence set forth in SEQ ID NO: 1011.

[0260] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more amino acid substitutions result in increased antibody half-life, increased ADCC activity, increased ADCP activity, or increased CDC activity compared with the Fc region without the one or more amino acid substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0261] In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this disclosure are referred to herein as “variants” or “clones”. In some embodiments, such variants or clones are derived from a sequence provided herein, for example, by affinity maturation, site directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants or clones are not derived from a sequence provided herein and may, for example, be isolated de novo according to the methods provided herein for obtaining antibodies.

[0262] The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art. See Schroeder et al. (2010) Allergy Clin.

[0263] Immunol. 125: S41-52, incorporated by reference in its entirety. The Fc region may be a naturally occurring Fc region, or an Fc region modified as described in the art or elsewhere in this disclosure. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. An " Fc polypeptide" of a dimeric Fc as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises an IgG CH2 and an IgG CH3 constant domain sequence. An Fc can be of the class IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgGi, IgGs, IgG, IgAi, and IgAz.

[0264] In certain embodiments, provided human IgGl Fc regions include an SRDEL (SEQ ID NO: 1013) allotype or an SREEM (SEQ ID NO: 1014) allotype.

[0265] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody. For example, an FcR can be a native sequence human FcR. Generally, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRUI subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Immunoglobulins of other isotypes can also be bound by certain FcRs (see, e.g., Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (IT AM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (reviewed in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0266] Modifications in the CH2 domain can affect the binding of FcRs to the Fc. A number of amino acid modifications in the Fc region are known in the art for selectively altering the affinity of the Fc for different Fcgamma receptors. In some aspects, the Fc comprises one or more modifications designed to promote selective binding of Fc-gamma receptors. Exemplary mutations that alter the binding of FcRs to the Fc are listed below (in EU numbering format):

[0267] • S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N, et al., J Immunol Methods. 2011 Feb 28;365(1-2):132-41);

[0268] • F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L (Stavenhagen JB, Gorlatov S, Tuaillon N, etal., Cancer Res. 2007 Sep 15;67(18):8882-90; Nordstrom JL, Gorlatov S, Zhang W, et al., Breast Cancer Res.

[0269] 2011 Nov 30;13(6): R123);

[0270] • F243L (Stewart R, Thom G, Levens M, et al. Protein Eng Des Sei. 2011 Sep;24(9):671- 8);

[0271] • S298A / E333A / K334A (Shields RL, Namenuk AK, Hong K, et al., J Biol Chem. 2001 Mar 2;276(9):6591-604);

[0272] • S239D / I332E / A330L, S239D / I332E (Lazar et al., (2006) Proc Natl Acad Sci USA.

[0273] 103(1 l):4005-10);

[0274] • S239D / S267E, S267E / L328F (Chu et al., (2008) Mol Immunol. 45(15):3926-33);

[0275] • S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / I33 2E, S239D / I332E / S298A, S239D / K326E / A330L / I332E / S298A, G236A / S239D / D270 L / I332E, S239E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135, herein incorporated by reference. Therapeutic Antibody Engineering (by William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 379, Oct 2012) lists mutations on page 283.

[0276] In some embodiments, an antibody described herein includes modifications intended to improve its ability to mediate effector function. Such modifications that can have this effect are known in the art and include afucosylation, or engineering of the affinity of the Fc towards an activating receptor, mainly FCGR3a for ADCC, and towards Clq for CDC. The following Table 5 summarizes various designs reported in the literature for effector function engineering.

[0277] Methods of producing antibodies with little or no fucose on the Fc glycosylation site (Asn 297 EU numbering) without altering the amino acid sequence are well known in the art. The GlymaX® technology (ProBioGen AG) is based on the introduction of a gene for an enzyme which deflects the cellular pathway of fucose biosynthesis into cells used for antibody production. This prevents the addition of the sugar “fucose” to the N-linked antibody carbohydrate part by antibody-producing cells, (von Horsten et al. (2010) Glycobiology. 20 (12): 1607-18). Examples of cell lines capable of producing defucosylated antibody include CHO-DG44 with stable overexpression of the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexylose reductase (RMD) {see von Horsten et al. (2010) supra) or Lecl3 CHO cells, which are deficient in protein fucosylation see Ripka et al. (1986) Arch. Biochem. Biophys. 249:533-545; U. S. Pat. Pub. No. 2003 / 0157108; WO 2004 / 056312; each of which is incorporated by reference in its entirety), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells {see Yamane-Ohnuki et al. (2004) Biotech. Bioeng. 87: 614-622; Kanda et al. (2006) Biotechnol. Bioeng. 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety). Another approach to obtaining antibodies with lowered levels of fucosylation can be found in U. S. patent 8,409,572, which teaches selecting cell lines for antibody production for their ability to yield lower levels of fucosylation on antibodies.

[0278] Antibodies can be fully afucosylated (meaning they contain no detectable fucose) or they can be partially afucosylated, meaning that the isolated antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15% or less than 5% of the amount of fucose normally detected for a similar antibody produced by a mammalian expression system.

[0279] In some aspects, an antibody provided herein comprises an IgGl domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgGl domain. Such Fc domains are known to have improved ADCC. See Shields et al., (2002) J. Biol. Chem.

[0280] 277:26733-26740, incorporated by reference in its entirety. In some aspects, such antibodies do not comprise any fucose at position Asn 297. The amount of fucose may be determined using any suitable method, for example as described in WO 2008 / 077546, incorporated by reference in its entirety.

[0281] In certain embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions which may improve ADCC, such as a substitution at one or more of positions 298, 333, and 334 of the Fc region. In some embodiments, an antibody provided herein comprises an Fc region with one or more amino acid substitutions at positions 239, 332, and 330, as described in Lazar et al., (2006) Proc. Natl. Acad. Sci. USA 103:4005-4010, incorporated by reference in its entirety.

[0282] Other illustrative glycosylation variants which may be incorporated into the antibodies provided herein are described, for example, in U. S. Pat. Pub. Nos. 2003 / 0157108, 2004 / 0093621, 2003 / 0157108, 2003 / 0115614, 2002 / 0164328, 2004 / 0093621, 2004 / 0132140, 2004 / 0110704, 2004 / 0110282, 2004 / 0109865; International Pat. Pub. Nos. 2000 / 61739, 2001 / 29246, 2003 / 085119, 2003 / 084570, 2005 / 035586, 2005 / 035778; 2005 / 053742, 2002 / 031140; Okazaki et al., J. Mol. Biol., 2004, 336:1239-1249; and Yamane-Ohnuki et al. (2004) supra; each of which is incorporated by reference in its entirety.

[0283] In some embodiments, an antibody provided herein comprises an Fc region with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Examples of such antibody variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764; each of which is incorporated by reference in its entirety.

[0284] Thus, in one embodiment, an antibody described herein can include a dimeric Fc that comprises one or more amino acid modifications as noted in Table 5 that may confer improved effector function. In another embodiment, the antibody can be afucosylated to improve effector function.

[0285] Table 5. CH2 Domains and Effector Function Engineering Reference Mutations Effect

[0286] Lu (2011), supra; Ferrara Afucosylated Increased ADCC (2011), supra; Mizushima

[0287] et al. (2011) Genes Cells.

[0288] 16(ll):1071-1080.

[0289] Lu (2011), supra S298A / E333A / K334A Increased ADCC Lu (2011), supra S298 A / E333 A / K334A / K326 A Increased ADCC Stavenhagen (2007), F243L / R292P / Y300L / V305I / P396L Increased ADCC supra

[0290] Nordstrom (2011), supra F243L / R292P / Y300L / L235V / P396L Increased ADCC Stewart (2011), supra F243L Increased ADCC Shields (2001), supra S298A / E333A / K334A Increased ADCC Lazar (2006), supra S239D / I332E / A330L Increased ADCC Lazar (2006), supra S239D / I332E Increased ADCC Bowles et al. (2006) AME-D, not specified mutations Increased ADCC Blood 108(8):2648-54

[0291] Heideret al. (2011) 37.1, mutations not disclosed Increased ADCC Blood 118(15):4159-68

[0292] Moore et al. (2010) S267E / H268F / S324T Increased CDC

[0293]

[0294] MAbs 2(2):181-9

[0295] Fc modifications intended to reduce FcgR and / or complement binding and / or effector function are known in the art. Recent publications describe strategies that have been used to engineer antibodies with reduced or silenced effector activity (see Strohl, WR (2009) Curr Opin Biotech 20:685-691, and Strohl, WR and Strohl LM, “Antibody Fc engineering for optimal antibody performance” In Therapeutic Antibody Engineering, Cambridge:

[0296] Woodhead Publishing (2012), pp 225-249). These strategies include reduction of effector function through modification of glycosylation, use of IgG2 / IgG4 scaffolds, or the introduction of mutations in the hinge or CH2 regions of the Fc. For example, U.S. Patent Publication No. 2011 / 0212087 (Strohl), International Patent Publication No. WO 2006 / 105338 (Xencor), U.S. Patent Publication No. 2012 / 0225058 (Xencor), U.S. Patent Publication No. 2012 / 0251531 (Genentech), and Strop et al ((2012) J. Mol. Biol. 420: 204-219), each of which is incorporated by reference in its entirety, describe specific modifications designed to reduce FcgR or complement binding to the Fc.

[0297] Specific, non-limiting examples of amino acid modifications intended to reduce FcgR or complement binding to the Fc include those identified in the following Table 6:

[0298] Table 6. Modifications Designed to Reduce FcgR or Complement Binding to the Fc Mutations

[0299] N297A

[0300] L234A / L235A

[0301] IGG2 V234A / G237A

[0302] IGG4 L235A / G237A / E318A

[0303] IGG4 S228P / L236E

[0304] IGG2 / IGG4

[0305] IGG2 H268Q / V309L / A330S / A331S C220S / C226S / C229S / P238S C226S / C229S / E3233P / L235V / L235A

[0306] E. coli production, non glyco

[0307] L234F / L235E / P331S

[0308] Hinge mutant, e.g., C226S / P230S

[0309] D265A

[0310] L235A / G237A

[0311]

[0312] L234A / L235A / G237A

[0313] L234A / L235A / P329G

[0314]

[0315] In some embodiments, an antibody provided herein comprises one or more alterations that may improve or diminish Clq binding and / or CDC. See U. S. Pat. No. 6,194,551; WO 99 / 51642; and Idusogie et al. (2000) J. Immunol. 164:4178-4184; each of which is incorporated by reference in its entirety.

[0316] In some embodiments, the OX40L antibody comprises a constant heavy chain sequence set forth in SEQ ID NO: 651. In some embodiments, the OX40L antibody comprises a constant heavy chain sequence set forth in SEQ ID NO: 924.

[0317] In some embodiments, the OX40L antibody comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

[0318] In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 924 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

[0319] In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 651, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 924, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738.

[0320] In some embodiments, the OX40L antibody included in a formulation described herein is an OX40L antibody described in International Patent Application Publication No. WO2024227174A2, which is incorporated herein by reference in its entirety.

[0321] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more amino acid substitutions result in an increase in one or more of antibody half-life, ADCC activity, ADCP activity, or CDC activity compared with the Fc region without the one or more amino acid substitutions. In certain embodiments, the one or more amino acid substitutions results in increased antibody half-life at pH 6.0 compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1 -fold, or 1.05-fold longer compared to an antibody comprising a wild-type Fc region. In certain embodiments, the antibody has an increased half-life that is about 10,000-fold, 1,000-fold, 500-fold, 100-fold, 50-fold, 20-fold, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4.5-fold, 4-fold, 3.5-fold, 3-fold, 2.5-fold, 2-fold, 1.95-fold, 1.9-fold, 1.85-fold, 1.8-fold, 1.75-fold, 1.7-fold, 1.65-fold, 1.6-fold, 1.55-fold, 1.50-fold, 1.45-fold, 1.4-fold, 1.35-fold, 1.3-fold, 1.25-fold, 1.2-fold, 1.15-fold, 1.1 -fold, or 1.05-fold longer compared to amlitelimab. The heavy and light chain variable region sequences of amlitelimab are set forth in Table 7.

[0322] Table 7. VH and VL Sequences of Amlitelimab

[0323] Antibody VH VL

[0324] Amlitelimab EVQLVESGGGLVQPGG DIQMTQSPSSLSASVGD SLRLSCAASGFTFSNYA RVTITCRASQSISSYLN MNWVRQAPGKGLEWV WYQQKPGKAPNLLIYA STISGSGGATRYADSVK ASSLQSGVPSRFSGSGS GRFTISRDNSRNTVYLQ ETDFTLTISSLQPEDFAT MNSLRVEDTAVFYCTK YYCQQSHSVSFTFGPGT DRLIMATVRGPYYYGM KVDIK DVWGQGTTVTVSS SEQ ID NO: 833

[0325] SEQ ID NO: 832

[0326]

[0327] In certain embodiments, an antibody described herein comprises a heavy chain constant domain having a means for increasing the half-life of the antibody.

[0328] In certain embodiments, the Fc region comprises one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a decrease in one or more of ADCC activity, ADCP activity, or CDC activity compared with the Fc region without the one or more substitutions.

[0329] In certain embodiments, the one or more amino acid substitutions is selected from the group consisting of S228P (SP), M252Y, S254T, T256E, T256D, T250Q, H285D, T307A, T307Q, T307R, T307W, L309D, Q411H, Q311V, A378V, E380A, M428L, N434A, N434S, N297A, D265A, L234A, L235A, and N434W. In certain embodiments, the one or more amino acid substitutions comprises a specific combination of amino acid substitutions selected from the group consisting of M428L / N434S (LS), M252Y / S254T / T256E (YTE), T250Q / M428L, T307A / E380A / N434A, T256D / T307Q (DQ), T256D / T307W (DW), M252Y / T256D (YD), T307Q / Q311V / A378V (QVV), T256D / H285D / T307R / Q311V / A378V (DDRVV), L309D / Q311H / N434S (DHS), S228P / L235E (SPLE), L234A / L235A (LALA), M428L / N434A (LA), L235A / G237A (LAGA), L234A / L235A / G237A (LALAGA), L234A / L235A / P329G (LALAPG), D265A / YTE, LALA / YTE, LAGA / YTE, LALAGA / YTE, LALAPG / YTE, N297A / LS, D265A / LS, LALA / LS, LALAGA / LS, LALAPG / LS, N297A / DHS, D265A / DHS, LALA / DHS, LAGA / DHS, LALAGA / DHS, LALAPG / DHS, SP / YTE, SPLE / YTE, SP / LS, SPLE / LS, SP / DHS, SPLE / DHS, N297A / LA, D265A / LA, LALA / LA, LAGA / LA, LALAGA / LA, LALAPG / LA, N297A / N434A, D265A / N434A, LALA / N434A, LAGA / N434A, LALAGA / N434A, LALAPG / N434A, N297A / N434W, D265A / N434W, LALA / N434W, LAGA / N434W, LALAGA / N434W, LALAPG / N434W, N297A / DQ, D265A / DQ, LALA / DQ, LAGA / DQ, LALAGA / DQ, LALAPG / DQ, N297A / DW, D265A / DW, LALA / DW, LAGA / DW, LALAGA / DW, LALAPG / DW, N297A / YD, D265A / YD, LALA / YD, LAGA / YD, LALAGA / YD, LALAPG / YD, T307Q / Q311V / A378V (QVV), N297A / QVV, D265A / QVV, LALA / QVV, LAGA / QVV, LALAGA / QVV, LALAPG / QVV, DDRVV, N297A / DDRVV, D265A / DDRVV, LALA / DDRVV, LAGA / DDRVV, LALAGA / DDRVV, and LALAPG / DDRVV.

[0330] Although the EU numbering system is typically used to identify the positions of the various Fc mutations described herein, direct numbering can also be used. For example, in certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 253, 255 and 257, respectively. In certain embodiments, an antibody described herein comprises an Fc region with LALA mutations at positions 235 and 236, respectively. In certain embodiments, an antibody described herein comprises an Fc region with YTE mutations at positions 253, 255 and 257 and with LALA mutations at positions 235 and 236. In certain embodiments, the OX40L antibody described herein comprises the heavy and light chain variable regions of Construct 114 and an Fc region comprising YTE mutations at positions 253, 255 and 257, respectively and with LALA mutations at positions 235 and 236, respectively (e.g., as shown in the heavy chain sequences of SEQ ID NOs: 1010 and 1011).

[0331] In certain embodiments, the Fc region binds an Fey Receptor selected from the group consisting of: FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and FcyRIIIb. In certain embodiments, the Fc region binds an Fey Receptor with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

[0332] Binding

[0333] The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including those described herein, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0334] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule (i.e., OX40L) and comparing it to binding to a non-target molecule. In some embodiments, the affinity of an anti-OX40L antibody for a non-target molecule is less than about 50% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody for a non-target molecule is less than about 40% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody for a non-target molecule is less than about 30% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody for a non-target molecule is less than about 20% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody for a non-target molecule is less than about 10% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody for a non-target molecule is less than about 1% of the affinity for OX40L. In some embodiments, the affinity of an anti-OX40L antibody for a non-target molecule is less than about 0.1% of the affinity for OX40L.

[0335] In certain embodiments, the antibody binds an OX40L sequence set forth in SEQ ID NO: 739. In certain embodiments, the antibody binds to an OX40L sequence set forth in SEQ ID NO: 739 with a KD of less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10-9M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to an OX40L sequence set forth in SEQ ID NO: 739 with a KD of less than or equal to about 1 x 10-10M, as measured by surface plasmon resonance (SPR). In certain embodiments, the antibody binds to human OX40L with a KD of less than or equal to about 1 x 10’9M, as measured by surface plasmon resonance (SPR).

[0336] In some embodiments, an antibody provided herein binds OX40L with a KD of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10’8M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an antibody provided herein binds OX40L with a KD of less than or equal to about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.95, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 x 10’9M, as measured by ELISA or any other suitable method known in the art.

[0337] In some embodiments, the KD of the antibody provided herein for the binding of OX40L is between about 0.001-0.01, 0.01-0.1, 0.01-0.05, 0.05-0.1, 0.1-0.5, 0.5-1, 0.25-0.75, 0.25-0.5, 0.5-0.75, 0.75-1, 0.75-2, 1.1-1.2, 1.2-1.3, 1.3-1.4, 1.4-1.5, 1.5-1.6, 1.6-1.7, 1.7-1.8, 1.8-1.9, 1.9-2, 1-2, 1-5, 2-7, 3-8, 3-5, 4-6, 5-7, 6-8, 7-9, 7-10, or 5-10 x 10’8M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an antibody provided herein binds OX40L with a KD of less than or equal to about 1 x 10-8M, or less than or equal to about 1 x 10-9M as measured by ELISA or any other suitable method known in the art.

[0338] In some embodiments, the antibody provided herein binds OX40L with a KD of less than or equal to about 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.98, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, or 0.0001 x IO’8M, or less, as measured by ELISA or any other suitable method known in the art. In some embodiments, the antibody provided herein binds OX40L with a KD between 5-3, 4-2, 3-1, 1.9-1.8, 1.8-1.7, 1.7-1.6, 1.6-1.5, 1.9-1.5, 1.5-1, 1-0.8, 1-0.5, 0.9-0.6, 0.7-0.4, 0.6-0.2, 0.5-0.3, 0.3-0.2, 0.2-0.1, 0.1-0.01, 0.01-0.001, or 0.001-0.0001 x 10’8M as measured by ELISA or any other suitable method known in the art.

[0339] In some embodiments, the antibody provided herein binds FcRn with an affinity at pH 7.4 compared to pH 6.0 at a ratio (pH 7.4 / pH 6.0) of about 10,000, 1,000, 500, 100, 50, 20, 10, 9, 8, 7, 6, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.50, 1.45, 1.4, 1.3, 1.2, 1.1, or 1.05, as measured by ELISA or any other suitable method known in the art. In some embodiments, the antibody provided herein binds FcRn with an affinity at pH 6.0 compared to pH 7.4 at a ratio (pH 6.0 / pH 7.4) of about 1-0.8, 1-0.5, 0.9-0.6, 0.7-0.4, 0.6-0.2, 0.5-0.3, 0.3-0.2, 0.2-0.1, 0.1-0.01, 0.01-0.001, or 0.001-0.0001 x W8M as measured by ELISA or any other suitable method known in the art.

[0340] Function

[0341] “Effector functions” refer to those biological activities mediated by the Fc region of an antibody, which activities may vary depending on the antibody isotype. Examples of antibody effector functions include receptor ligand blocking, agonism, or antagonism, Clq binding to activate complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody-dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP).

[0342] Pharmaceutical Formulations and Methods of Manufacture Thereof

[0343] In some embodiments, the present disclosure provides pharmaceutical formulations that comprise a therapeutically effective amount of an OX40L antibody disclosed herein. The pharmaceutical formulation comprises one or more excipients and / or surfactants and is maintained at a certain pH. Non-limiting examples of an “excipient,” as used herein, include any non-therapeutic agent added to the formulation to provide a desired physical or chemical property, for example, pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration.

[0344] Methods of manufacturing pharmaceutical formulations of the disclosure are also contemplated. The method can include adjusting the matrix of an intermediate preparation of the disclosure (e.g., changing the buffer composition and / or the concentration of a purified preparation of an OX40L antibody), such as by Ultrafiltration and Diafiltration (UFDF), to increase a concentration of an OX40L antibody.

[0345] In certain aspects, described herein is a method of manufacturing an intermediate preparation of an OX40L antibody comprising: (a) obtaining a purified preparation of the OX40L antibody; and (b) adjusting the matrix of the purified preparation of step (a), wherein adjusting the matrix of comprises performing Ultrafiltration and Diafiltration (UFDF) with a diafiltration buffer comprising a histidine buffer and arginine or a salt solution thereof, wherein the diafiltration buffer is at pH of from about 5.4 to about 7.0 (e.g., about 5.4 to about 6.0), thereby obtaining the intermediate preparation of the OX40L antibody.

[0346] In certain embodiments, the intermediate preparation of the OX40L antibody has a higher concentration of the OX40L antibody relative to the purified preparation.

[0347] In certain embodiments, the method of manufacturing further comprises: (c) formulating the intermediate preparation to obtain a formulation of the OX40L antibody. In certain embodiments, the formulation of the OX40L antibody comprises the formulation of any one of the aspects or embodiments described herein.

[0348] In certain embodiments, the histidine buffer comprises a histidine and a histidine salt. In certain embodiments, the histidine is L-histidine. In certain embodiments, the histidine salt is L-histidine HC1 monohydrate. In some embodiments, the histidine buffer (e.g., a combination L-histidine and L-histidine HC1 buffer) is at a concentration between about 5 mM and about 20 mM (e.g., at a concentration between 5 mM and 19 mM, between 5 mM and 18 mM, between 5 mM and 17 mM, between 5 mM and 16 mM, between 5 mM and 15 mM, between 5 mM and 14 mM, between 5 mM and 13 mM, between 5 mM and 12 mM, between 5 mM and 11 mM, between 5 mM and 10 mM, between 6 mM and 20 mM, between 7 M and 20 mM, between 8 mM and 20 mM, between 9 mM and 20 mM, between 10 mM and 20 mM, between 6 mM and 19 mM, between 7 mM and 18 mM, between 8 mM and 17 mM, between 9 mM and 16 mM, and between 10 mM and 15 mM). In some embodiments, the histidine buffer (e.g., a combination L-histidine and L-histidine HC1 buffer) is at a concentration of about 10 mM. In certain embodiments, the arginine is L-arginine. In certain embodiments, the arginine is an L-arginine salt solution. In certain embodiments, the L-arginine salt solution salt solution comprises HC1 monohydrate. In certain embodiments, the L-arginine salt solution is at a concentration between about 40 mM and about 250 mM (e.g., at a concentration between 50 mM and 250 mM, between 60 mM and 250 mM, between 70 mM and 250 M, between 80 mM and 250 M, between 90 M and 250 M, between 100 mM and 250 mM, between 110 mM and 250 mM, between 120 mM and 250 mM, between 40 mM and 240 mM, between 40 mM and 230 mM, between 40 mM and 220 mM, between 40 mM and 220 mM, between 40 mM and 210 mM, between 40 mM and 200 mM, between 40 mM and 190 mM, between 40 mM and 180 mM, between 40 mM and 170 mM, between 40 mM and 160 mM, between 40 mM and 150 mM, between 40 mM and 140 mM, between 40 mM and 130 mM, between 40 mM and 120 mM, between 50 mM and 200 mM, between 60 mM and 150 mM, between 70 mM and 125 mM, or between 80 mM and 100 mM, such as 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mM). In certain embodiments, the L-arginine salt solution is at a concentration of about 120 mM.

[0349] Excipients, Surfactants, and pH

[0350] Excipients may be selected for their suitability for intravenous or subcutaneous administration, providing the necessary stabilization, buffering capacity, viscosity, and tonicity. The formulation can maintain or improve the stability of the OX40L antibody and can provide a sterile solution suitable for subcutaneous or intravenous administration. In some embodiments the excipients and / or surfactants contained in the formulation are pharmacopeial grade excipients. In some embodiments, the excipients in the formulation comprise a histidine buffer (e.g., a combination L-histidine and L-histidine HC1 buffer), an acetate buffer, and / or a succinate buffer; arginine and / or methionine (e.g., L-arginine and / or L-methionine) or a salt solution thereof (e.g., a solution of arginine and / or methionine or a salt thereof); and a polysorbate or a poloxamer. In certain embodiments, the formulation further comprises EDTA. In certain embodiments, the formulation further comprises EGTA. In certain embodiments, the formulation further comprises about 0.01 mM to about 1 mM EDTA or EGTA (e.g.., about 0.01 mM to about 0.9 mM, about 0.01 mM to about 0.8 mM, about 0.01 mM to about 0.7 mM, about 0.01 mM to about 0.6 mM, about 0.01 mM to about 0.5 mM, about 0.01 mM to about 0.4 mM, about 0.01 mM to about 0.3 mM, about 0.01 mM to about 0.25mM, about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.15 mM, about 0.01 mM to about 0.1 mM, about 0.01 mM to about 0.09 mM, about 0.01 mM to about 0.08 mM, about 0.01 mM to about 0.07 mM, about 0.01 mM to about 0.06 mM, about 0.01 mM to about 0.05 mM, about 0.02 mM to about 1 mM, about 0.03 mM to about 1 mM, about 0.04 mM to about 1 mM, about 0.05 mM to about 1 mM, about 0.06 mM to about 1 mM, about 0.07 mM to about 1 mM, about 0.08 mM to about 1 mM, about 0.09 mM to about 1 mM, about 0.1 mM to about 1 mM, about 0.15 mM to about 1 mM, about 0.2 mM to about 1 mM, about 0.25 mM to about 1 mM, about 0.3 mM to about 1 mM, about 0.4 mM to about 1 mM, about 0.5 mM to about 1 mM, about 0.6 mM to about 1 mM, about 0.7 mM to about 1 mM, about 0.8 mM to about 1 mM, or about 0.9 mM to about 1 mM EDTA or EGTA). In certain embodiments, the formulation further comprises about 0.05 mM EDTA. In certain embodiments, the formulation further comprises about 0.05 mM EGTA. In some embodiments, the formulation further comprises a sugar or sugar alcohol.

[0351] The one or more excipients in the pharmaceutical formulation of the present invention can comprise a buffering agent. The term “buffering agent,” as used herein, refers to one or more components that when added to an aqueous solution is able to protect the solution against variations in pH when adding acid or alkali, or upon dilution with a solvent. In addition to histidine buffers, acetate buffers, and succinate buffers, in certain embodiments, phosphate buffers, glycinate buffers, carbonate buffers, citrate buffers and the like can be used. In some embodiments, sodium, potassium or ammonium ions can serve as counterion. In certain embodiments, the buffer or buffer system, such as a histidine buffer (e.g., a combination L-histidine and L-histidine HC1 buffer), acetate buffer, and / or succinate buffer, comprises at least one buffer that has a buffering range that overlaps fully or in part with the range of between about 5.0 to about 7.0 (e.g., 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8. 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0). In certain embodiments, the pH of the buffer is between about 5.5 and about 6.5. In certain embodiments, the pH of the buffer is between about 5.8 and about 6.2. In certain embodiments, the pH of the buffer is about 6.0.

[0352] In some embodiments, the buffer has a pH of about 5.0. In some embodiments, the buffer has a pH of about 5.1. In some embodiments, the buffer has a pH of about 5.2. In some embodiments, the buffer has a pH of about 5.3. In some embodiments, the buffer has a pH of about 5.4. In some embodiments, the buffer has a pH of about 5.5. In some embodiments, the buffer has a pH of about 5.6. In some embodiments, the buffer has a pH of about 5.7. In some embodiments, the buffer has a pH of about 5.8. In some embodiments, the buffer has a pH of about 5.9. In some embodiments, the buffer has a pH of about 6.0. In some embodiments, the buffer has a pH of about 6.1. In some embodiments, the buffer has a pH of about 6.2. In some embodiments, the buffer has a pH of about 6.3. In some embodiments, the buffer has a pH of about 6.4. In some embodiments, the buffer has a pH of about 6.5. In some embodiments, the buffer has a pH of about 6.6. In some embodiments, the buffer has a pH of about 6.7. In some embodiments, the buffer has a pH of about 6.8. In some embodiments, the buffer has a pH of about 6.9. In some embodiments, the buffer has a pH of about 7.0. Under the rules of scientific rounding, a pH greater than or equal to 5.45 and smaller than or equal to 5.55 is rounded as 5.5.

[0353] In some embodiments, the histidine buffer (e.g., a combination L-histidine and L-histidine HC1 buffer), acetate buffer, and / or succinate buffer is at a concentration between about 5 mM and about 20 mM (e.g., at a concentration between 5 mM and 19 mM, between 5 mM and 18 mM, between 5 mM and 17 mM, between 5 mM and 16 mM, between 5 mM and 15 mM, between 5 mM and 14 mM, between 5 mM and 13 mM, between 5 mM and 12 mM, between 5 mM and 11 mM, between 5 mM and 10 mM, between 6 mM and 20 mM, between 7 mM and 20 mM, between 8 mM and 20 mM, between 9 mM and 20 mM, between 10 mM and 20 mM, between 6 mM and 14 mM, between 7 mM and 13 mM, between 8 mM and 12 mM, between 9 mM and 11 mM, between 6 mM and 19 mM, between 7 mM and 18 mM, between 8 mM and 17 mM, between 9 mM and 16 mM, or between 10 mM and 15 mM). In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration between 6 mM and 19 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration between 7 mM and 18 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration between 8 mM and 17 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration between 9 mM and 16 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration between 10 mM and 15 mM.

[0354] In some embodiments, the histidine buffer (e.g., a combination L-histidine and L-histidine HC1 buffer), acetate buffer, and / or succinate buffer is at a concentration of about 1 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 2 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 3 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 4 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 5 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 6 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 7 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 8 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 9 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 10 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 11 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 12 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 13 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 14 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 15 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 16 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 17 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 18 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 19 mM. In some embodiments, the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 20 mM.

[0355] In some embodiments the formulation comprises a histidine buffer {e.g., a combination L-histidine and L-histidine HC1 buffer), acetate buffer, or succinate buffer. In some embodiments the formulation comprises a histidine buffer. In some embodiments, the histidine buffer comprises L-histidine and L-histidine HC1. In some embodiments the formulation comprises an acetate buffer. In some embodiments, the formulation comprises a succinate buffer.

[0356] In some embodiments, a histidine buffer {e.g., L-histidine and L-histidine HC1 monohydrate) acts as a buffering agent. In some embodiments, the histidine buffer comprises a histidine and a histidine salt. In some embodiments, the histidine is L-histidine. In some embodiments, the histidine salt is L-histidine HC1 monohydrate.

[0357] In some embodiments, the formulation comprises a histidine buffer at a concentration of about 10 mM to about 15 mM (e.g., about 10 mM), wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate.

[0358] In some embodiments, the formulation comprises methionine. In some embodiments, the methionine is L-methionine.

[0359] In some embodiments, the methionine {e.g., L-methionine) is at a concentration between about 5 mM and about 20 mM {e.g., at a concentration between 5 mM and 19 mM, between 5 mM and 18 mM, between 5 mM and 17 mM, between 5 mM and 16 mM, between 5 mM and 15 mM, between 5 mM and 14 mM, between 5 mM and 13 mM, between 5 mM and 12 mM, between 5 mM and 11 mM, between 5 mM and 10 mM, between 6 mM and 20 mM, between 7 mM and 20 mM, between 8 mM and 20 mM, between 9 mM and 20 mM, between 10 mM and 20 mM, between 6 mM and 14 mM, between 7 mM and 13 mM, between 8 mM and 12 mM, between 9 mM and 11 mM, between 6 mM and 19 mM, between 7 mM and 18 mM, between 8 mM and 17 mM, between 9 mM and 16 mM, or between 10 mM and 15 mM). In some embodiments, the L-methionine is at a concentration between 6 mM and 19 mM. In some embodiments, the L-methionine is at a concentration between 7 mM and 18 mM. In some embodiments, the L-methionine is at a concentration between 8 mM and 17 mM. In some embodiments, the L-methionine is at a concentration between 9 mM and 16 mM. In some embodiments, the L-methionine is at a concentration between 10 mM and 15 mM.

[0360] In some embodiments, the methionine (e.g., L-methionine) is at a concentration of about 1 mM. In some embodiments, the L-methionine is at a concentration of about 2 mM. In some embodiments, the L-methionine is at a concentration of about 3 mM. In some embodiments, the L-methionine is at a concentration of about 4 mM. In some embodiments, the L-methionine is at a concentration of about 5 mM. In some embodiments, the L-methionine is at a concentration of about 6 mM. In some embodiments, the L-methionine is at a concentration of about 7 mM. In some embodiments, the L-methionine is at a concentration of about 8 mM. In some embodiments, the L-methionine is at a concentration of about 9 mM. In some embodiments, the L-methionine is at a concentration of about 10 mM. In some embodiments, the L-methionine is at a concentration of about 11 mM. In some embodiments, the L-methionine is at a concentration of about 12 mM. In some embodiments, the L-methionine is at a concentration of about 13 mM. In some embodiments, the L-methionine is at a concentration of about 14 mM. In some embodiments, the L-methionine is at a concentration of about 15 mM. In some embodiments, the L-methionine is at a concentration of about 16 mM. In some embodiments, the L-methionine is at a concentration of about 17 mM. In some embodiments, the L-methionine is at a concentration of about 18 mM. In some embodiments, the L-methionine is at a concentration of about 19 mM. In some embodiments, the L-methionine is at a concentration of about 20 mM.

[0361] In some embodiments, the formulation comprises arginine. In some embodiments, the arginine is L-arginine. In some embodiments, the formulation comprises an L-arginine salt solution (e.g., a solution of an L-arginine salt). In some embodiments, the L-arginine or L-arginine salt solution acts as a viscosity modulator or a stabilizer. In some embodiments, the L-arginine salt solution salt solution comprises HC1 monohydrate. In some embodiments, the arginine (e.g., L-arginine) salt solution is at a concentration between about 40 mM and about 250 mM (e.g., at a concentration between 50 mM and 250 mM, between 60 mM and 250 mM, between 70 mM and 250 mM, between 80 mM and 250 mM, between 90 mM and 250 mM, between 100 mM and 250 mM, between 110 mM and 250 mM, between 120 mM and 250 mM, between 40 mM and 240 mM, between 40 mM and 230 mM, between 40 mM and 220 mM, between 40 mM and 220 mM, between 40 mM and 210 mM, between 40 mM and 200 mM, between 40 mM and 190 mM, between 40 mM and 180 mM, between 40 mM and 170 mM, between 40 mM and 160 mM, between 40 mM and 150 mM, between 40 mM and 140 mM, between 40 mM and 130 mM, between 40 mM and 120 mM, between 50 mM and 200 mM, between 60 mM and 150 mM, between 70 mM and 125 mM, between 80 mM and 100 mM, or about 90 mM, 100 mM, 110 mM, or 120 mM). For example, in some embodiments, the arginine (e.g., L-arginine) salt solution is at a concentration between 70 mM and 130 mM.

[0362] In some embodiments, the L-arginine salt solution is at a concentration of about 40 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 50 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 60 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 70 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 80 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 90 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 100 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 110 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 120 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 125 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 130 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 140 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 150 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 200 mM. In some embodiments, the L-arginine salt solution is at a concentration of about 250 mM.

[0363] In some embodiments, the formulation comprises L-arginine HC1 at a concentration of about 70 mM to about 130 mM (e.g., about 120 mM) and L-methionine at a concentration of about 10 mM to about 15 mM (e.g., about 10 mM).

[0364] The one or more excipients in the pharmaceutical formulation disclosed herein further comprises a surfactant. The term “surfactant,” as used herein, refers to a surface active molecule containing both a hydrophobic portion (e.g., alkyl chain) and a hydrophilic portion (e.g., carboxyl and carboxylate groups). Surfactants are useful in pharmaceutical formulations for reducing aggregation of a therapeutic protein. Surfactants suitable for use in the pharmaceutical formulations are generally non-ionic surfactants and include, but are not limited to, polysorbates (e.g., polysorbates 20 or 80); poloxamers (e.g., poloxamer 188); sorbitan esters and derivatives; Triton; sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetadine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauramidopropyl-cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, pahnidopropyl-, or isostearamidopropylbetaine (e.g., lauroamidopropyl); myristamidopropyl-, pahnidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; and the MONAQUAT™ series (Mona Industries, Inc., Paterson, N. J.); polyethylene glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics, PF68, etc.). In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the surfactant is polysorbate 80. In certain embodiments, the surfactant is a poloxamer. In certain embodiments, the surfactant is poloxamer 188.

[0365] In some embodiments, a polysorbate or poloxamer acts as a surfactant. In some embodiments, the polysorbate or poloxamer is at a concentration between about 0.01% w / v and about 0.15% w / v (e.g., at a concentration between 0.01% w / v and 0.14% w / v, between 0.01% w / v and 0.13% w / v, between 0.01% w / v and 0.12% w / v, between 0.01% w / v and 0.11% w / v, between 0.01% w / v and 0.10% w / v, between 0.01% w / v and 0.09% w / v, between 0.01% w / v and 0.08% w / v, between 0.01% w / v and 0.07% w / v, between 0.01% w / v and 0.06% w / v, between 0.01% w / v and 0.05% w / v, between 0.02% w / v and 0.08% w / v, between 0.03% w / v and 0.07% w / v, between 0.04% w / v and 0.06% w / v, between 0.02% w / v and 0.14% w / v, 0.03% w / v and 0.13% w / v, 0.04% w / v and 0.12% w / v, 0.05% w / v and 0.11% w / v, or about 0.1% w / v). In some embodiments, the polysorbate or poloxamer is at a concentration between 0.02% w / v and 0.14% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration between 0.03% w / v and 0.13% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration between 0.04% w / v and 0.12% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration between 0.05% w / v and 0.11% w / v.

[0366] In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.01% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.02% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.03% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.04% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.05% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.06% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.07% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.08% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.09% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.1% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.11% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.12% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.13% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.14% w / v. In some embodiments, the polysorbate or poloxamer is at a concentration of about 0.15% w / v.

[0367] In some embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. In some embodiments, the polysorbate is polysorbate 20. In some embodiments, the polysorbate is polysorbate 40. In some embodiments, the polysorbate is polysorbate 60. In some embodiments, the polysorbate is polysorbate 80.

[0368] In some embodiments, the formulation comprises polysorbate 80 at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v, or about 0.05% w / v).

[0369] In certain embodiments the poloxamer is at a concentration between about 0.1 mg / mL and about 1.0 mg / mL (e.g., at a concentration of about 0.1 mg / mL to about 0.9 mg / mL, about 0.1 mg / mL to about 0.8 mg / mL, about 0.1 mg / mL to about 0.7 mg / mL, about 0.1 mg / mL to about 0.6 mg / mL, about 0.1 mg / mL to about 0.5 mg / mL, about 0.2 mg / mL to about 1.0 mg / mL, about 0.3 mg / mL to about 1.0 mg / mL, about 0.4 mg / mL to about 1.0 mg / mL, about 0.5 mg / mL to about 1.0 mg / mL, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg / mL). In certain embodiments, the poloxamer is at a concentration of about 0.1 mg / mL to about 0.5 mg / mL. In certain embodiments, the poloxamer is at a concentration of about 0.5 mg / mL. In some embodiments, the poloxamer is poloxamer 188 or poloxamer 407. In some embodiments, the poloxamer is poloxamer 188.

[0370] The one or more excipients in the pharmaceutical formulation of the present invention further comprises a sugar or sugar alcohol. Sugars and sugar alcohols are useful in pharmaceutical formulations as a thermal stabilizer. In certain embodiments, the pharmaceutical formulation comprises a sugar, for example, a monosaccharide (glucose, xylose, or erythritol), a disaccharide (e.g., sucrose, trehalose, maltose, or galactose), or an oligosaccharide (e.g., stachyose). In specific embodiments, the pharmaceutical formulation comprises sucrose. In certain embodiments, the pharmaceutical composition comprises a sugar alcohol, for example, a sugar alcohol derived from a monosaccharide (e.g., mannitol, sorbitol, or xylitol), a sugar alcohol derived from a disaccharide (e.g., lactitol or maltitol), or a sugar alcohol derived from an oligosaccharide. In specific embodiments, the pharmaceutical formulation comprises sucrose.

[0371] In some embodiments, a sugar or sugar alcohol (e.g., sucrose) acts as a stabilizer. In some embodiments, the sugar or sugar alcohol is at a concentration between about 1% w / v and about 10% w / v (e.g., at a concentration between 1% w / v and 9% w / v, between 1% w / v and 8% w / v, between 1% w / v and 7% w / v, between 1% w / v and 6% w / v, between 1% w / v and 5% w / v, between 2% w / v and 8% w / v, between 3% w / v and 7% w / v, between 3% w / v and 6% w / v, or about 3% w / v, about 4% w / v, about 5% w / v, or about 6% w / v). In some embodiments, the sugar or sugar alcohol is at a concentration between 3% w / v and 6% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration between 2% w / v and 4% w / v.

[0372] In some embodiments, the sugar or sugar alcohol is at a concentration of about 1% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 2% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 3% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 4% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 5% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 6% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 7% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 8% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 9% w / v. In some embodiments, the sugar or sugar alcohol is at a concentration of about 10% w / v.

[0373] In some embodiments, the sugar or sugar alcohol is a disaccharide. In some embodiments, the disaccharide is sucrose.

[0374] In some embodiments, the formulation is adjusted to final volume in water for injection (WFI).

[0375] In certain embodiments, the drug product is diluted in an aqueous carrier suitable for the route of administration, e.g., intravenous administration or subcutaneous administration. Exemplary carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer's solution, or dextrose solution. In one embodiment, when the pharmaceutical formulation is prepared for intravenous administration, the pharmaceutical formulation can be diluted in a 5% dextrose solution (D5W).

[0376] Exemplary Formulations

[0377] In some embodiments, the pharmaceutical formulation comprises: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL (e.g., at a concentration of about 130 mg / mL to about 250 mg / mL, about 135 mg / mL to about 245 mg / mL, about 140 mg / mL to about 240 mg / mL, about 145 mg / mL to about 235 mg / mL, about 150 mg / mL to about 230 mg / mL, about 150 mg / mL to about 225 mg / mL, about 150 mg / mL to about 220 mg / mL, about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 150 mg / mL to about 175 mg / mL, about 150 mg / mL to about 170 mg / mL, about 150 mg / mL to about 165 mg / mL, about 150 mg / mL to about 160 mg / mL, about 155 mg / mL to about 200 mg / mL, about 160 mg / mL to about 200 mg / mL, about 165 mg / mL to about 200 mg / mL, about 170 mg / mL to about 200 mg / mL, about 175 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 165 mg / mL to about 220 mg / mL, about 170 mg / mL to about 220 mg / mL, about 175 mg / mL to about 220 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL); (b) a histidine buffer (e.g., combination L-histidine and L-histidine HC1 buffer), an acetate buffer (e.g., combination acetic acid and sodium acetate trihydrate), or a succinate buffer (e.g., combination succinic acid and sodium succinate hexahydrate); (c) arginine and / or methionine (e.g., L-arginine and / or L-methionine) or a salt solution thereof (e.g., a solution of arginine and / or methionine or a salt thereof); and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0.

[0378] In some embodiments, the pharmaceutical formulation consists of: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL; (b) a histidine buffer, an acetate buffer, or a succinate buffer; (c) arginine and / or methionine or a salt solution thereof; and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0.

[0379] In some embodiments, the pharmaceutical formulation comprises: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL (e.g., at a concentration of about 130 mg / mL to about 250 mg / mL, about 135 mg / mL to about 245 mg / mL, about 140 mg / mL to about 240 mg / mL, about 145 mg / mL to about 235 mg / mL, about 150 mg / mL to about 230 mg / mL, about 150 mg / mL to about 225 mg / mL, about 150 mg / mL to about 220 mg / mL, about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 150 mg / mL to about 175 mg / mL, about 150 mg / mL to about 170 mg / mL, about 150 mg / mL to about 165 mg / mL, about 150 mg / mL to about 160 mg / mL, about 155 mg / mL to about 200 mg / mL, about 160 mg / mL to about 200 mg / mL, about 165 mg / mL to about 200 mg / mL, about 170 mg / mL to about 200 mg / mL, about 175 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 165 mg / mL to about 220 mg / mL, about 170 mg / mL to about 220 mg / mL, about 175 mg / mL to about 220 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL); (b) arginine and / or methionine e.g., L-arginine and / or L-methionine) or a salt solution thereof (e.g., a solution of arginine and / or methionine or a salt thereof); and (c) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0.

[0380] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL (e.g., at a concentration of about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, or 220 mg / mL); (b) a histidine buffer (e.g., a histidine buffer comprising L-histidine and L-histidine HC1 monohydrate) at a concentration of about 5 mM to about 15 mM (e.g., about 8 mM to about 12 mM, about 10 mM to about 15 mM, or about 10 mM); (c) arginine (e.g., an L-arginine salt solution) at a concentration of about 70 mM to about 130 mM (e.g., about 120 mM); (d) methionine (e.g., L-methionine) at a concentration of about 5 mM to about 15 mM (e.g., about 8 mM to about 12 mM, about 10 mM to about 15 mM, or about 10 mM); and (e) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v, or about 0.5% w / v), wherein the formulation is at a pH of about 5.8 to about 6.2 (e.g., about 6.0).

[0381] In some embodiments, the pharmaceutical formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at pH of about 6.0.

[0382] In some embodiments, the formulation consists of: (a) an OX40L antibody at a concentration of about 150 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0383] In some embodiments, the pharmaceutical formulation comprises: (a) an OX40L antibody at a concentration of about 180 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0384] In some embodiments, the formulation consists of: (a) an OX40L antibody at a concentration of about 180 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0385] In some embodiments, the formulation comprises: (a) an OX40L antibody present at a concentration of about 200 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0386] In some embodiments, the formulation consists of: (a) an OX40L antibody present at a concentration of about 200 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0387] In some embodiments, the formulation comprises: (a) an OX40L antibody present at a concentration of about 220 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0388] In some embodiments, the formulation consists of: (a) an OX40L antibody present at a concentration of about 220 mg / mL; (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; and (e) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0389] In some embodiments, the pharmaceutical formulation comprises: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL (e.g., at a concentration of about 130 mg / mL to about 250 mg / mL, about 135 mg / mL to about 245 mg / mL, about 140 mg / mL to about 240 mg / mL, about 145 mg / mL to about 235 mg / mL, about 150 mg / mL to about 230 mg / mL, about 150 mg / mL to about 225 mg / mL, about 150 mg / mL to about 220 mg / mL, about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 150 mg / mL to about 175 mg / mL, about 150 mg / mL to about 170 mg / mL, about 150 mg / mL to about 165 mg / mL, about 150 mg / mL to about 160 mg / mL, about 155 mg / mL to about 200 mg / mL, about 160 mg / mL to about 200 mg / mL, about 165 mg / mL to about 200 mg / mL, about 170 mg / mL to about 200 mg / mL, about 175 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 165 mg / mL to about 220 mg / mL, about 170 mg / mL to about 220 mg / mL, about 175 mg / mL to about 220 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL); (b) a histidine buffer, an acetate buffer, or a succinate buffer; (c) arginine and / or methionine or a salt solution thereof; and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0, and wherein the OX40L antibody comprises: a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:368.

[0390] In some embodiments, the pharmaceutical formulation consists of: (a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL; (b) a histidine buffer, an acetate buffer, or a succinate buffer; (c) arginine and / or methionine or a salt solution thereof; and (d) a polysorbate or a poloxamer, wherein the formulation is at a pH of about 5.0 to about 7.0, and wherein the OX40L antibody comprises: a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:368.

[0391] In certain embodiments, the formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL (e.g., at a concentration of about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, or 220 mg / mL); (b) arginine (e.g., an L-arginine salt solution) at a concentration of about 70 mM to about 130 mM (e.g., about 120 mM); (c) methionine (e.g., L-methionine) at a concentration of about 5 mM to about 15 mM (e.g., about 8 mM to about 12 mM, about 10 mM to about 15 mM, or about 10 mM); and (d) a polysorbate (e.g., polysorbate 80) at a concentration of about 0.04% w / v to about 0.12% w / v (e.g., about 0.04% w / v to about 0.06% w / v, or about 0.5% w / v), wherein the formulation is at a pH of about 5.8 to about 6.2 (e.g., about 6.0). In some embodiments, the pharmaceutical formulation comprises: (a) an OX40L antibody at a concentration of about 150 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05% w / v, at pH of about 6.0.

[0392] In some embodiments, the pharmaceutical formulation comprises: (a) an OX40L antibody at a concentration of about 180 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0393] In some embodiments, the formulation comprises: (a) an OX40L antibody present at a concentration of about 200 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0394] In some embodiments, the formulation comprises: (a) an OX40L antibody present at a concentration of about 220 mg / mL; (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; and (d) a polysorbate 80 at a concentration of about 0.05% w / v, at a pH of about 6.0.

[0395] In certain embodiments, the formulation further comprises EDTA. In certain embodiments, the formulation further comprises EGTA. In certain embodiments, the formulation further comprises about 0.01 mM to about 1 mM EDTA or EGTA (e.g.., about 0.01 mM to about 0.9 mM, about 0.01 mM to about 0.8 mM, about 0.01 mM to about 0.7 mM, about 0.01 mM to about 0.6 mM, about 0.01 mM to about 0.5 mM, about 0.01 mM to about 0.4 mM, about 0.01 mM to about 0.3 mM, about 0.01 mM to about 0.25mM, about 0.01 mM to about 0.2 mM, about 0.01 mM to about 0.15 mM, about 0.01 mM to about 0.1 mM, about 0.01 mM to about 0.09 mM, about 0.01 mM to about 0.08 mM, about 0.01 mM to about 0.07 mM, about 0.01 mM to about 0.06 mM, about 0.01 mM to about 0.05 mM, about 0.02 mM to about 1 mM, about 0.03 mM to about 1 mM, about 0.04 mM to about 1 mM, about 0.05 mM to about 1 mM, about 0.06 mM to about 1 mM, about 0.07 mM to about 1 mM, about 0.08 mM to about 1 mM, about 0.09 mM to about 1 mM, about 0.1 mM to about 1 mM, about 0.15 mM to about 1 mM, about 0.2 mM to about 1 mM, about 0.25 mM to about 1 mM, about 0.3 mM to about 1 mM, about 0.4 mM to about 1 mM, about 0.5 mM to about 1 mM, about 0.6 mM to about 1 mM, about 0.7 mM to about 1 mM, about 0.8 mM to about 1 mM, or about 0.9 mM to about 1 mM EDTA or EGTA). In certain embodiments, the formulation further comprises about 0.05 mM EDTA. In certain embodiments, the formulation further comprises about 0.05 mM EGTA. In certain embodiments, the formulation comprises: (a) an OX40L antibody present at a concentration of about 150 mg / mL to about 220 mg / mL (e.g., at a concentration of about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, or 220 mg / mL); (b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate; (c) an L-arginine salt solution at a concentration of about 120 mM; (d) L-methionine at a concentration of about 10 mM; (e) a polysorbate 80 at a concentration of about 0.05% w / v; and (f) about 0.05 mM EDTA, wherein the formulation is at a pH of about 6.0. In certain embodiments, the OX40L antibody is present at a concentration of about 150 mg / mL. In certain embodiments, the OX40L antibody is present at a concentration of about 180 mg / mL. In certain embodiments, the OX40L antibody is present at a concentration of about 200 mg / mL. In certain embodiments, the OX40L antibody is present at a concentration of about 220 mg / mL.

[0396] In certain embodiments, the formulation comprises: (a) an OX40L antibody present at a concentration of about 150 mg / mL to about 220 mg / mL (e.g., at a concentration of about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, about 190 mg / mL to about 200 mg / mL, about 180 mg / mL to about 220 mg / mL, about 185 mg / mL to about 220 mg / mL, about 190 mg / mL to about 220 mg / mL, about 195 mg / mL to about 220 mg / mL, or about 200 mg / mL to about 220 mg / mL, such as 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, or 220 mg / mL); (b) an L-arginine salt solution at a concentration of about 120 mM; (c) L-methionine at a concentration of about 10 mM; (d) a polysorbate 80 at a concentration of about 0.05% w / v; and (e) about 0.05 mM EDTA, wherein the formulation is at a pH of about 6.0. In certain embodiments, the OX40L antibody is present at a concentration of about 150 mg / mL. In certain embodiments, the OX40L antibody is present at a concentration of about 180 mg / mL. In certain embodiments, the OX40L antibody is present at a concentration of about 200 mg / mL. In certain embodiments, the OX40L antibody is present at a concentration of about 220 mg / mL.

[0397] In certain embodiments, the formulation further comprises a sugar or sugar alcohol. In some embodiments, the OX40L antibody comprises a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:368. In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419. In some embodiments, the OX40L antibody comprises a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489. In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419 and a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 or SEQ ID NO: 924. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 924. In some embodiments, the OX40L antibody comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 924 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 651, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 924, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738. In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012. In some embodiments, the OX40L antibody comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 1010 or SEQ ID NO: 1011. In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012 and a heavy chain comprising the sequence set forth in SEQ ID NO: 1010. The C-terminal lysine in SEQ ID NO: 1010 may not be present if cleavage occurs during manufacture or after administration (which would result in the heavy chain sequence of SEQ ID NO: 1011). In some embodiments, the OX40L antibody comprises a light chain comprising the sequence set forth in SEQ ID NO: 1012 and a heavy chain comprising the sequence set forth in SEQ ID NO: 1011.

[0398] Stability

[0399] The formulations of the present invention exhibit high levels of stability. A formulation is stable when the OX40L antibody within the formulation retains an acceptable degree of physical property, chemical structure, and / or biological function after storage under defined conditions.

[0400] Exemplary methods to determine stability of the OX40L antibody in the formulation are described in the Examples of the present disclosure. Additionally, stability of the protein can be assessed by measuring the binding affinity of the OX40L antibody to its targets or the biological activity of the OX40L antibody in certain in vitro assays.

[0401] The formulation can be prepared and stored as a liquid formulation. In certain embodiments, the pharmaceutical formulation is a Equid formulation for storage frozen (-20 to -70 °C), under refrigerated conditions (typically 2-8 °C), or at room temperature (typically 20-26 °C) before preparation for administration. In certain embodiments, the formulation is a liquid formulation for storage at a suitable temperature and protected from light.

[0402] In some embodiments, the anti-OX40L antibody in the formulation remains stable at about 2 °C to about 5 °C (e.g., 2, 3, 4, or 5 °C) for at least six months (e.g., at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months), as determined by size exclusion chromatography (e.g., SEC-HPLC or SEC-UPLC).

[0403] In some embodiments, the anti-OX40L antibody in the formulation remains stable at about 2 °C to about 5 °C (e.g., 2, 3, 4, or 5 °C) for at least one year (e.g., at least 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 years), as determined by size exclusion chromatography (e.g., SEC-HPLC or SEC-UPLC).

[0404] In some embodiments, the anti-OX40L antibody in the formulation remains stable at about 2 °C to about 5 °C (e.g., 2, 3, 4, or 5 °C) for at least two years, as determined by size exclusion chromatography (e.g., SEC-HPLC or SEC-UPLC).

[0405] In some embodiments, the anti-OX40L antibody in the formulation remains stable at about 2 °C to about 5 °C (e.g., 2, 3, 4, or 5 °C) for at least three years, as determined by size exclusion chromatography (e.g., SEC-HPLC or SEC-UPLC).

[0406] In some embodiments, at least about 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more) of the native form of the antibody (i.e., the antibody monomer) is recovered after about six months of storage at about 5° C, as determined by size exclusion chromatography (e.g., SEC-UPLC). In some embodiments, at least about 95% (e.g., 95%, 96%, 97%, 98%, 99%, or more) of the native form of the antibody (i.e., the antibody monomer) is recovered after about six months of storage at about 5° C, as determined by size exclusion chromatography (e.g., SEC-UPLC). In some embodiments, at least about 98% of the native form of the antibody (i.e., the antibody monomer) is recovered after about six months of storage at about 5° C, as determined by size exclusion chromatography (e.g., SEC-UPLC).

[0407] Dosage Forms

[0408] Prior to pharmaceutical use, the formulation can be diluted in an aqueous carrier if suitable for the route of administration. In some embodiments, an OX40L antibody is fully formulated for subcutaneous administration (i.e., no diluents are added), and thus is identical in composition to the formulation described herein. Alternatively, if suitable for the route of administration, e.g., for intravenous or subcutaneous administration, the OX40L antibody may be further diluted in an appropriate carrier prior to pharmaceutical use. For intravenous or subcutaneous administration, suitable carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline solution, Ringer’s solution, or dextrose solution. For example, when the formulation is prepared for intravenous administration, the pharmaceutical formulation may comprises a dextrose solution, such as a 5% dextrose solution (D5W). In certain embodiments, the diluted formulation is isotonic and suitable for administration by intravenous infusion, e.g., D5W. In certain embodiments, the formulation is diluted in about 50 mL D5W, 100 mL D5W, 150 mL D5W, 200 mL D5W, 250 mL D5W, 300 mL D5W, 350 mL D5W, 400 mL D5W, 450 mL D5W, 500 mL D5W, or 1 L D5W.

[0409] The formulation comprises the OX40L antibody at a concentration suitable for storage. In certain embodiments, the formulation comprises the OX40L antibody at a concentration between about 125 mg / mL and about 250 mg / mL (e.g., at a concentration of about 130 mg / mL to about 250 mg / mL, about 135 mg / mL to about 245 mg / mL, about 140 mg / mL to about 240 mg / mL, about 145 mg / mL to about 235 mg / mL, about 150 mg / mL to about 230 mg / mL, about 150 mg / mL to about 225 mg / mL, about 150 mg / mL to about 220 mg / mL, about 150 mg / mL to about 215 mg / mL, about 150 mg / mL to about 210 mg / mL, about 150 mg / mL to about 205 mg / mL, about 150 mg / mL to about 200 mg / mL, about 150 mg / mL to about 195 mg / mL, about 150 mg / mL to about 190 mg / mL, about 150 mg / mL to about 185 mg / mL, about 150 mg / mL to about 180 mg / mL, about 150 mg / mL to about 175 mg / mL, about 150 mg / mL to about 170 mg / mL, about 150 mg / mL to about 165 mg / mL, about 150 mg / mL to about 160 mg / mL, about 155 mg / mL to about 200 mg / mL, about 160 mg / mL to about 200 mg / mL, about 165 mg / mL to about 200 mg / mL, about 170 mg / mL to about 200 mg / mL, about 175 mg / mL to about 200 mg / mL, about 180 mg / mL to about 200 mg / mL, about 185 mg / mL to about 200 mg / mL, or about 190 mg / mL to about 200 mg / mL, such as 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250 mg / mL). In certain embodiments, the OX40L antibody is at a concentration of between about 150 mg / mL and about 220 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of between about 160 mg / mL and about 220 mg / mL (e.g., between 170 mg / mL and 210 mg / mL, 180 mg / mL and 200 mg / mL, or about 190 mg / mL). In certain embodiments, the OX40L antibody is at a concentration of between about 150 mg / mL and about 200 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of about 150 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of about 180 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of about 200 mg / mL. In certain embodiments, the OX40L antibody is at a concentration of about 220 mg / mL.

[0410] Formulations described herein may be included in, e.g., a vial, bag, bottle, or on-body device. In some embodiments, the vial is a syringe. In some embodiments, the syringe is a prefilled syringe. In some embodiments, the vial is an autoinjector. In some embodiments, the vial is a cartridge (e.g., an autoinjector cartridge, such as a pre-filled autoinjector cartridge). In some embodiments, the vial is a pen. In some embodiments, the vial is a glass vial or a polymer vial. In certain embodiments, formulations described herein may be included in and administered by pens, autoinjectors, including autoinjector syringes and cartridges, and on-body devices (e.g., an on-body injector). In some embodiments, when an on-body device is used for administration, up to 5 mL of the formulation may be present in the device.

[0411] In some embodiments, an extractable volume of the vial e.g., prefilled syringe) is between about 1.0 mL and about 5.0 mL. In some embodiments, an extractable volume of the vial (e.g., prefilled syringe) is between about 1.0 mL and about 3.0 mL. In some embodiments, the extractable volume of the vial is about 2.0 mL. As used herein, the “extractable volume” of the vial is the amount that can be withdrawn from the receptacle. The fill volume is greater than the extractable volume to ensure that the extractable volume can be obtained.

[0412] In certain embodiments, the formulation is packaged in a vial (e.g., a pen, syringe, autoinjector, cartridge, glass vial, or polymer vial). In certain embodiments, the vial comprises an overfill to allow for complete removal of the intended dose. In certain embodiments, the vial comprises an overfill of 5 to 35%, 10 to 30%, 15 to 25%, or 10 to 20%. In a particular embodiment, the vial comprises an overfill of about 20%.

[0413] In certain embodiments, the formulation is a liquid formulation. In certain embodiments, the amount of OX40L antibody in the container (e.g., syringe (e.g., pre-filled syringe), autoinjector, cartridge (e.g., an autoinjector cartridge, such as a pre-filled autoinjector cartridge), pen, glass vial, or polymer vial) is suitable for administration as a single dose. In certain embodiments, the amount of OX40L antibody in the container is suitable for administration in multiple doses. In certain embodiments, the amount of OX40L antibody from multiple containers (e.g., 2, 3, or 4 containers) is administered for a single dose. In certain embodiments, the pharmaceutical formulation comprises the OX40L antibody in an amount of 0.1 to 200 mg. In certain embodiments, the formulation comprises the OX40L antibody in an amount of 1 to 200 mg, 10 to 200 mg, 20 to 200 mg, 50 to 200 mg, 100 to 200 mg, 100 to 500 mg, 200 to 500 mg, 500 to 2000 mg, 1000 to 2000 mg, 0.1 to 1000 mg, 1 to 1000 mg, 10 to 1000 mg, 20 to 1000 mg, 50 to 1000 mg, 100 to 1000 mg, 200 to 1000 mg, 400 to 1000 mg, 500 to 1000 mg, 750 to 1000 mg, 0.1 to 500 mg, 1 to 500 mg, 10 to 500 mg, 20 to 500 mg, 50 to 500 mg, 100 to 500 mg, 200 to 500 mg, 300 to 500 mg, 0.1 to 200 mg, 1 to 200 mg, 10 to 200 mg, 20 to 200 mg, 50 to 200 mg, 100 to 200 mg, 0.1 to 100 mg, 1 to 100 mg, 10 to 100 mg, 20 to 100 mg, 50 to 100 mg, 0.1 to 50 mg, 1 to 50 mg, 10 to 50 mg, 20 to 50 mg, 0.1 to 20 mg, 1 to 20 mg, 10 to 20 mg, 0.1 to 10 mg, 1 to 10 mg, or 0.1 to 1 mg. In certain embodiments, the formulation comprises the OX40L antibody in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 160 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or about 2000 mg.

[0414] Methods of Use and Methods of Treatment

[0415] The present application provides compositions comprising a formulation or vial described herein for use in the treatment of an inflammatory disorder or disease. In some embodiments, the present application also provides compositions comprising a formulation or vial {e.g., pre-filled syringe or autoinjector) described herein for use in methods of treating inflammatory, allergic, and immunologic diseases, such as atopic dermatitis, in a patient in need thereof. In certain embodiments, the patient has been diagnosed with moderate-to-severe atopic dermatitis. In certain embodiments, the patient has had moderate-to-severe atopic dermatitis for at least one year. In certain embodiments, the patient is a pediatric patient.

[0416] In certain embodiments, the patient has one or more of: (a) an Eczema Area and Severity Index (EASI) Score of >10 e.g., an EASI score of >16 or an EASI score of >10 and <16), (b) an Investigator Global Assessment (IGA) score (also referred to as a validated Investigator Global Assessment- AD (vIGA-AD) score) of >3 and (c) a body surface area (BSA) (i.e., AD affecting a body surface area (BSA)) of >10%. In certain embodiments, the patient has an Eczema Area and Severity Index (EASI) Score of >10. In certain embodiments, the patient has an Eczema Area and Severity Index (EASI) Score of >16. In certain embodiments, the patient has an Eczema Area and Severity Index (EASI) Score of >10 and less than 16. In certain embodiments, the patient has an EASI score of >16 and <21. In certain embodiments, the patient has an EASI score of >21 and <48. In certain embodiments, the patient has an Investigator Global Assessment (IGA) score of >3. In certain embodiments, the patient has a body surface area (BSA) of >10%. In certain embodiments, moderate-to-severe AD is defined as an EASI score of >16, a vIGA-AD score of >3, and AD affecting a body surface area (BSA) of >10%. In certain embodiments, the patient has or has been diagnosed as having moderate AD. In certain embodiments, the patient has or has been diagnosed as having severe AD. In certain embodiments, the patient has a vIGA-AD score of 3 at Baseline. In certain embodiments, the patient has a vIGA-AD score of 4 at Baseline.

[0417] The “Investigator Global Assessment” or “IGA” is an assessment measure used globally to rate the severity of the patient’s AD (Simpson E, et al. J Am Acad Dermatol. 2020;83(3):839-846). It is based on a 5-point scale ranging from 0 (clear) to 4 (severe) and a score is selected using descriptors that best describe the overall appearance of the lesions at a given time point. It is not necessary that all characteristics under Morphological Description be present. The IGA can be conducted prior to conducting the EASI and BSA assessments.

[0418] The “Eczema Area and Severity Index” or “EASI” is a measure used in clinical settings to assess the severity and extent of AD (Hanifin et al., Exp Dermatol. 2001; 10: 11-18). EASI is a composite index with scores ranging from 0 to 72, with the higher values indicating more severe and / or extensive disease. The severity of erythema, induration / papulation, excoriation, and lichenification can be assessed by a clinician or other medical professional on a scale of 0 (absent) to 3 (severe) for each of the 4 body areas: head and neck, trunk, upper limbs, and lower limbs, with half points allowed. In addition, the extent of AD involvement in each of the 4 body areas can be assessed as a percentage by body surface area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. A total score (0 - 72) is assigned based on the sum of total scores for each of the four body region scores.

[0419] The “Scoring of Atopic Dermatitis” or “SCORAD” is a validated clinical tool for assessing the extent and intensity of AD developed by the European Task Force on Atopic Dermatitis (Consensus report of the European Task Force on Atopic Dermatitis.

[0420] Dermatology. 1993; 186(l):23-31). There are 3 components to the assessment: (i) the extent of AD is assessed as a percentage of each defined body area and reported as the sum of all areas, with a score ranging from 0 to 100 (assigned as “A” in the overall SCORAD calculation); (ii) the severity of 6 symptoms of AD: redness, swelling, oozing / crusting, excoriation, skin thickening / lichenification, dryness. Each item is graded as follows: none (0), mild (1), moderate (2), or severe (3) (for a maximum of 18 total points, assigned as “B” in the overall SCORAD calculation); (iii) subjective assessment of itch and of sleeplessness is recorded for each symptom using a visual analogue scale (VAS), where 0 is no itch (or sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum possible score of 20 (assigned as “C” in the overall SCORAD calculation). The SCORAD Index formula is: A / 5 + 7B / 2 + C. The maximal score of the SCORAD Index is 103.

[0421] Pruritus Numerical Rating Scale (NRS) (also referred to as the Itch Numeric Rating Scale) is an 11 -point scale used by patients (and if applicable, with help of parents / caregiver if required) to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable” (Phan NQ, et al. Acta Derm Venereol 2012; 92: 502-507). Assessments are recorded by the patient daily using an electronic diary. The baseline pruritus NRS is determined based on the average of daily Pruritus NRS during the 7 days immediately preceding baseline. A minimum of 4 daily scores out of the 7 days immediately preceding baseline is required for this calculation.

[0422] Sleep loss scale rates patient’s sleep loss due to pruritus on a 5-point Likert scale (with scores ranging from 0 [not at all], 1 [a little], 2 [moderately], 3 [quite a bit], to 4 [unable to sleep at all]). Assessments will be recorded daily by the patient using an electronic diary.

[0423] The Patient-Oriented Eczema Measure (POEM) is a 7-item, validated, questionnaire completed by the patient (and if applicable, with help of parents / caregiver if required) to assess disease symptoms over the last week (Centre of Evidence Based Dermatology. POEM - Patient Oriented Eczema Measure. Available at www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx). Patients are asked to respond to 7 questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping. All 7 answers carry equal weight with a total possible score from 0 to 28 (answers scored as: No days=0; 1- 2 days = 1; 3-4 days = 2; 5-6 days = 3; everyday = 4). A high score is Indicative of a poor quality of life. POEM responses are captured weekly using an electronic diary.

[0424] The Dermatology Life Quality Index (DLQI) is a 10-item, validated questionnaire completed by the patient or caregiver, used to assess the impact of skin disease on the quality of life of the patient (Finlay, A. Y. and Khan, G. K. 1994. Clinical and Experimental Dermatology 1993 Sep 23; 19:210-216). The 10 questions cover the following topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, and treatment, over the previous week. Each question is scored from 0 to 3 (“not at all,” “a little,” “a lot,” and “very much”), giving a total score ranging from 0 to 30. A high score is indicative of a poor quality of life.

[0425] In certain embodiments, methods described herein comprise determining one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Investigator Global Assessment (IGA). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Body Surface Area (BSA). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Pruritus Numerical Rating Scale (NRS). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Sleep loss scale, SCORing Atopic Dermatitis (SCORAD). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Patient Oriented Eczema Measure (POEM). In certain embodiments, methods described herein comprise determining the following characteristic of the patient at baseline and during and after the induction period: Dermatology Life Quality Index (DLQI).

[0426] In certain embodiments, a patient described herein is determined to have one or more of the following characteristics of the patient at baseline and during and after the induction period: Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Body Surface Area (BSA), Pruritus Numerical Rating Scale (NRS), Sleep loss scale, SCORing Atopic Dermatitis (SCORAD), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI). In certain embodiments, a patient herein is determined to have a characteristic Eczema Area and Severity Index (EASI) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Investigator Global Assessment (IGA) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Body Surface Area (BSA) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Pruritus Numerical Rating Scale (NRS) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Sleep loss scale, SCORing Atopic Dermatitis (SCORAD) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Patient Oriented Eczema Measure (POEM) at baseline and during and after the induction period. In certain embodiments, a patient herein is determined to have a characteristic Dermatology Life Quality Index (DLQI) at baseline and during and after the induction period.

[0427] In an aspect, the present application provides methods of contacting OX40L with an OX40L antibody, such as a human, humanized, or chimeric antibody, which results in inhibition of OX40L binding to an OX40L receptor (OX40) expressed on a cell.

[0428] In an aspect, the present application provides a formulation or vial described herein for use in the treatment of an inflammatory disorder or disease selected from the group consisting of asthma; idiopathic pulmonary fibrosis; alopecia areata; chronic sinusitis with nasal polyps; (e.g., Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)); Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA); Prurigo Nodularis (PN); Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO); Bullous Pemphigoid (BP); Cold Inducible Urticaria (ColdU); Allergic Fungal Rhinosinusitis (AFRS); Allergic Bronchopulmonary Aspergillosis (ABPA); Chronic Obstructive Pulmonary Disease (COPD); an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis; lupus; rheumatoid arthritis (RA); psoriasis; hidradenitis suppurativa; celiac disease; systemic sclerosis; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; and nephrogenic systemic fibrosis.

[0429] In an aspect, the present application provides methods for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a formulation described herein.

[0430] In some embodiments, the inflammatory disorder or disease is atopic dermatitis. In some embodiments, the inflammatory disorder or disease is asthma; idiopathic pulmonary fibrosis; alopecia areata; chronic sinusitis with nasal polyps; (e.g., Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)); Chronic Rhinosinusitis without Nasal Polyps (CRSsNP); eosinophilic esophagitis (EoE); an Eosinophilic gastrointestinal disorder or disease (EGID), such as Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), or Eosinophilic Gastroenteritis (EGE); Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA); Prurigo Nodularis (PN); Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO); Bullous Pemphigoid (BP); Cold Inducible Urticaria (ColdU); Allergic Fungal Rhinosinusitis (AFRS); Allergic Bronchopulmonary Aspergillosis (ABPA); Chronic Obstructive Pulmonary Disease (COPD); an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis; lupus; rheumatoid arthritis (RA); psoriasis; hidradenitis suppurativa; celiac disease; systemic sclerosis; allergic rhinitis; eosinophilic fasciitis; scleromyxedema; scleredema; or nephrogenic systemic fibrosis.

[0431] In some embodiments, the inflammatory disorder or disease is asthma. In some embodiments, the inflammatory disorder or disease is idiopathic pulmonary fibrosis. In some embodiments, the inflammatory disorder or disease is alopecia areata. In some embodiments, the inflammatory disorder or disease is chronic sinusitis with nasal polyps (e.g., Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)). In some embodiments, the inflammatory disorder or disease is Chronic Rhinosinusitis without Nasal Polyps (CRSsNP). In some embodiments, the inflammatory disorder or disease is eosinophilic esophagitis (EoE). In some embodiments, the inflammatory disorder or disease is an Eosinophilic gastrointestinal disorder or disease (EGID). In some embodiments, the inflammatory disorder or disease is Eosinophilic Gastritis (EoG). In some embodiments, the inflammatory disorder or disease is Eosinophilic Enteritis (EoN). In some embodiments, the inflammatory disorder or disease is Eosinophilic Colitis (EoC). In some embodiments, the inflammatory disorder or disease is Eosinophilic Gastroenteritis (EGE). In some embodiments, the inflammatory disorder or disease is Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA). In some embodiments, the inflammatory disorder or disease is Prurigo Nodularis (PN). In some embodiments, the inflammatory disorder or disease is of Chronic Spontaneous Urticaria (CSU). In some embodiments, the inflammatory disorder or disease is Chronic Pruritis of Unknown Origin (CPUO). In some embodiments, the inflammatory disorder or disease is Bullous Pemphigoid (BP). In some embodiments, the inflammatory disorder or disease is Cold Inducible Urticaria (ColdU). In some embodiments, the inflammatory disorder or disease is Allergic Fungal Rhinosinusitis (AFRS). In some embodiments, the inflammatory disorder or disease is Allergic Bronchopulmonary Aspergillosis (ABPA). In some embodiments, the inflammatory disorder or disease is Chronic Obstructive Pulmonary Disease (COPD). In some embodiments, the inflammatory disorder or disease is an inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis. In some embodiments, the inflammatory disorder or disease is lupus. In some embodiments, the inflammatory disorder or disease is rheumatoid arthritis (RA). In some embodiments, the inflammatory disorder or disease is psoriasis. In some embodiments, the inflammatory disorder or disease is hidradenitis suppurativa. In some embodiments, the inflammatory disorder or disease is celiac disease. In some embodiments, the inflammatory disorder or disease is systemic sclerosis. In some embodiments, the inflammatory disorder or disease is allergic rhinitis. In some embodiments, the inflammatory disorder or disease is eosinophilic fasciitis. In some embodiments, the inflammatory disorder or disease is scleromyxedema. In some embodiments, the inflammatory disorder or disease is scleredema. In some embodiments, the inflammatory disorder or disease is nephrogenic systemic fibrosis.

[0432] In an aspect, the present application provides methods for treating a pathology associated with elevated levels of OX40L in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a formulation described herein.

[0433] In an aspect, the present application provides methods for treating a pathology associated with OX40L activity in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a formulation described herein.

[0434] In an aspect, the present application provides methods of reducing biological activity of OX40L in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a formulation described herein.

[0435] In an aspect, the present application provides methods of preventing an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of a formulation described herein.

[0436] In some embodiments, the formulation is administered subcutaneously or intravenously. Kits

[0437] The present application provides kits comprising any one or more of the antibody formulations described herein and instructions for use. In some embodiments, the kits further contain a component selected from any of secondary antibodies, reagents for immunohistochemistry analysis, a pharmaceutically acceptable excipient, and an instruction manual and any combination thereof. In one specific embodiment, the kit comprises a formulation comprising any one or more of the antibodies described herein, with one or more pharmaceutically acceptable excipients.

[0438] In one embodiment, the kit comprises: (i) a dose of any of the formulations described herein (e.g., any one of the formulations described herein in unit dosage form) and (ii) a means for delivery of the formulation to a human. In some embodiments, the means is a syringe (e.g., a pre-filled syringe). In some embodiments, the means is an autoinjector. In some embodiments, the means is an on-body injector. In some embodiments, the kit is used to treat an inflammatory disorder or disease in a human patient.

[0439] EXAMPLES

[0440] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and is not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0441] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T. E. Creighton, Proteins: Structures and Molecular Properties (W. H. Freeman and Company, 1993); A. L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rdEd. (Plenum Press) Vols A and B(1992).

[0442] Example 1: Excipient and Surfactant Screening Study An excipient and surfactant screening experiment was performed to screen optimal excipients and surfactants to stabilize the protein, i.e., Construct 114, under conditions including accelerated thermal, freeze / thaw, and / or agitation conditions. This was done by evaluating the stability of Construct 114 under stress conditions. The study design and formulation details are set forth in Table 8 and Table 9, which provide an overview of the excipient and surfactant screening study plan, including the details for Formulations Fl through F7, as well as the attributes, conditions, and sampling points. The histidine buffer used in the Formulations was 20 mM L-histidine / L-histidine-HCl (“20mM His”). As used throughout the tables below, “Histidine” or “His” refers to L-histidine / L-histidine HC1, “Arg. HQ” refers to “L-arginine HC1,” “Met” refers to L-methionine, “EDTA” and “EDTA*2Na” are used interchangeably, “PS80” refers to polysorbate 80 and “Pl 88” refers to poloxamer 188.

[0443] All of the formulations described in Table 8 below contained 150 mg / mL of Construct 114. Construct 114 comprises a VH domain comprising the amino acid sequence set forth in SEQ ID NO: 419, a VL domain comprising the amino acid sequence set forth in SEQ ID NO: 489, a constant heavy chain sequence set forth SEQ ID NO: 924, and a constant light chain sequence set forth in SEQ ID NO: 738, as shown in the heavy chain sequence set forth in SEQ ID NO: 1010 and the light chain sequence set forth in SEQ ID NO: 1012. A C- terminal lysine is present in SEQ ID NO: 924 (which corresponds to the C-terminal lysine in SEQ ID NO: 1010), which may be cleaved off during manufacture, resulting in the constant heavy chain sequence of SEQ ID NO: 651. Accordingly, Construct 114 may contain the constant heavy chain sequence set forth in SEQ ID NO: 924 or SEQ ID NO: 651, or a mixture thereof.

[0444] Table 8. Formulations

[0445] Formulations

[0446] No. Cone.

[0447] Buffer pH Excipients Surfactants 120 mM Arg. HCl, 10 mM Met., 0.05

[0448] Fl 5.4

[0449] mM EDTA-2Na

[0450] 150 120 mM Arg. HCl, 10 mM Met., 0.05

[0451] F2 20mM His 5.8 0.04% (w / v) PS80 mg / mL mM EDTA-2Na

[0452] 120 mM Arg. HCl, 10 mM Met., 0.05

[0453] F3 6.2

[0454] mM EDTA-2Na

[0455]

[0456] F4 5.8 120 mM Arg. HCl, 10 mM Met.

[0457] 80 mM Arg. HCl, 10 mM Met., 3% w / v

[0458] F5 5.8

[0459] sucrose

[0460] F6 5.8 120 mM Arg. HCl, 10 mM Met. 0.5 mg / mLP188 F7 5.8 6% w / v sucrose 0.04% (w / v) PS80

[0461]

[0462] “F listidine” and “His” = L-histic ine / L-histidine HCL; “Arg. HCl” = “L-arginine HQ” “Met” = L-methionine; “EDTA” and “EDTA-2Na” are used interchangeably

[0463] “PS80” = polysorbate 80; “P188” = poloxamer 188

[0464] Table 9. Study Design

[0465] Sampling Points and Assay Attributes Condition

[0466] TO 2 Weeks 3 Weeks 3 Months 40 °C X X, Y, Z, P X, Y, Z, P Thermal 25 °C X X, Y, Z*, P X, Y, Z, P

[0467] 2-8 °C X X, Y, Z*, P X, Y, Z, P X, Y, Z,

[0468] 5 Cycles

[0469] Freeze / Thaw -70 °C to RT W, P

[0470] X, Y, P

[0471] 300 rpm, 3 Days

[0472] Agitation

[0473] 25 °C X, Y, P

[0474] X = Appearance, SE-UPLC, Caliper-SDS (NR & R), iCIEF

[0475] Y = Protein concentration

[0476] Z = PS80, Potency (only for certain formulations)

[0477] W = pH, Osmolality, Viscosity (20 °C)

[0478] P = Sub-visible particles (MFI, ~1.5mL)

[0479]

[0480] Table 10 sets forth the appearance results (i.e., slightly yellow (SY), slightly opalescent liquid (SO), and FP (free of visible particles) for Formulations Fl through F7. In brief, all samples remained slightly yellow, slightly opalescent, and free of visible particles after 3 months incubation at 5 °C, 25 °C, or 40 °C, freeze / thaw for 5 cycles, and / or agitation for 3 days. Table 10. Appearance Results

[0481] Excipients Appearance

[0482] No. Buffer &

[0483] pH 40 °C 25 °C 5 °C

[0484] surfactants TO A-3D FT-5 C (w / v) 2W 3W 3M 2W 3W 3M 2W 3W 3M

[0485] 120 mM

[0486] Arg. HCl,

[0487] 10 mM Met,

[0488] Fl SY, SY, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SY, SO,

[0489] 5.4 0.05 mM

[0490] SO, FP SO, FP FP FP FP FP FP FP FP FP SO, FP FP EDTA-2Na,

[0491] 0.04% (w / v)

[0492] PS80

[0493] 120 mM

[0494] Arg. HCl,

[0495] 10 mM Met,

[0496] F2 SY, SY, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SY, SO,

[0497] 5.8 0.05 mM

[0498] SO, FP SO, FP FP FP FP FP FP FP FP FP SO, FP FP EDTA-2Na,

[0499] 0.04% (w / v)

[0500] PS80

[0501] 120 mM

[0502] 20 mM

[0503] Arg. HCl,

[0504] Histidine

[0505] 10 mM Met,

[0506] F3 SY, SY, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SY, SO,

[0507] 6J 0.05 mM

[0508] SO, FP SO, FP FP FP FP FP FP FP FP FP SO, FP FP EDTA-2Na,

[0509] 0.04% (w / v)

[0510] PS80

[0511] 120mM

[0512] Arg. HCl,

[0513] F4 SY, SY, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SY, SO,

[0514] 5.8 10 mM Met, SO, FP SO, FP FP FP FP FP FP FP FP FP SO, FP FP 0.04% (w / v)

[0515] PS80

[0516] 80 mM

[0517] Arg. HCl,

[0518] F5 SY, SY, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SY, SO,

[0519] 5.8 10 mM Met,

[0520] SO, FP SO, FP FP FP FP FP FP FP FP FP SO, FP FP 3% w / v

[0521]

[0522] sucrose, 0.04% (w / v)

[0523] PS80

[0524] 120 mM

[0525] Arg. HCl,

[0526] SY, SY, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SY, SO, F6 5.8 10 mM Met,

[0527] SO, FP SO, FP FP FP FP FP FP FP FP FP SO, FP FP 0.5 mg / mL

[0528] Pl 88

[0529] 6% w / v

[0530] sucrose, SY, SY, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SY, SO, F7 5.8 0.04% (w / v) SO, FP SO, FP FP FP FP FP FP FP FP FP SO, FP FP

[0531]

[0532] PS80

[0533] SY: Slightly yellow; SO: Slightly opalescent liquid; FP: free of visible particles. Table 11 sets forth the protein concentration results for Formulations Fl through F7. The protein concentration values remained comparable for all conditions.

[0534] Table 12 sets forth the sub- visible particle results for Formulations Fl through F7 with particles. No substantial changes of sub-visible particles were observed in all formulations after 3 months incubation at 5 °C and 25 °C. An increase in particles at 40 °C signals the stability-indicating attribute of this assay under stressed conditions.

[0535] Table 13 sets forth the Size-Exclusion Ultra Performance Liquid Chromatography (SE-UPLC) results for Formulations Fl through F7 at 40 °C through 3 months. After incubation at 40 °C for 3 months, 6.4-9.3% monomer % decreases were observed, with 2.3-5.8% high molecular weight (HMW) increase and 3.5-4.7% low molecular weight (LMW) increase in all formulations. F2-F6 showed no substantial differences, while higher monomer % decrease was observed in Fl and F7.

[0536] Table 14 sets forth the SE-UPLC results for Formulations Fl through F7 at 25 °C through 3 months. After incubation at 25 °C for 3 months, 0.7- 1.4% monomer % decrease was observed in all formulations when compared with TO. F7 showed a higher monomer % decrease among all formulations.

[0537] Table 15 sets forth the SE-UPLC results for Formulations Fl through F7 at 5 °C through 3 months. No substantial changes of SE-UPLC monomer % were observed in all formulations after 5°C-3M.

[0538] Table 16 sets forth the capillary electrophoresis sodium dodecyl sulfate (CE-SDS) Caliper-NR results for Formulations Fl through F7. No substantial changes were observed in all formulations after 5 °C-3M, freeze / thaw cycles (FT-5 cycles) and agitation for 3 days (A-3D). After 25 °C-3M, no substantial changes were observed in F1-F6 except F7 with 2.3% CE-SDS Caliper-NR purity decreases. After incubation at 40 °C for 3 months, 10.0-11.7% CE-SDS Caliper-NR purity % decreases were observed in all formulations. No substantial differences were observed among all 7 formulations.

[0539] Table 17 sets forth the CE-SDS Caliper-R results for Formulations Fl through F7. No substantial changes were observed in all formulations after 25C-3M, 5C-3M, FT-5 cycles and A-3D. Decreases of 3.3-4.7% CE-SDS Caliper-R purity % was observed after 3 months incubation at 40 °C compared with TO. No substantial differences were observed among all 7 formulations. Table 11. Protein Concentration Results

[0540] Protein concentration (mg / mL)

[0541] No.

[0542] TO A-3D FT-5C 40 °C -3 W 40 °C-3 M 25 °C-3 W 25 °C-3 M 5 °C-3 W 5 °C-3 M

[0543] Fl 152.9 155.0 156.2 156.8 155.6 155.9 157.2 157.1 156.0

[0544] F2 152.3 152.0 154.0 153.8 153.2 155.0 152.1 153.8 152.5

[0545] F3 153.2 153.4 153.8 152.8 155.3 155.9 156.1 155.4 162.8

[0546] F4 152.5 153.7 155.3 154.0 154.0 153.8 154.9 153.2 154.6

[0547] F5 152.8 151.8 154.7 153.4 155.5 153.6 154.6 155.0 154.7

[0548] F6 153.2 152.4 155.4 151.9 154.3 152.5 154.9 157.0 153.6

[0549] F7 153.4 153.4 155.6 154.2 155.4 154.3 156.0 155.8 152.9

[0550]

[0551] Table 12. Sub-visible Particle Results

[0552] Sub-visible particles (particles / mL, > 2 pm / > 10 pm / > 25 pm)

[0553] TO 40°C-3 W 40°C-3M 25°C-3 W 25°C-3 M 5°C-3W 5°C-3 M No. Excipients & Buffer pH surfactants (w / v) >10 >25 > 10 >25 >10 >25 >10 >25 > 10 >25 >10 >25 >10 >25 pm pm pm pm pm pm gm pm pm pm gm gm gm gm 120 mM Arg. HCl,

[0554] Fl 4 22 32 14 12 2

[0555] 5.4 10 mM Met, 25 9 9 5 15 0 0 0 0.05 mM EDTA-2Na,

[0556] 0.04% (w / v) PS80

[0557] 120 mM Arg. HCl,

[0558] 14 4 34 4 3210 mM Met, 5 0 10 5 0 27 23 0 7 F2 5.8 0.05 mM EDTA'2Na,

[0559] 0.04% (w / v) PS80

[0560] 120 mM Arg. HCl,

[0561] 10 mM Met, 2 2 4 19 9 0 76 15 9 55 7 10 60 5 F3 6.2 0.05 mM EDTA-2Na,

[0562] 20 mM 0.04% (w / v) PS80

[0563] Histidine

[0564] 120 mM Arg. HCl,

[0565] 2 2 4 2 23 5 9 9 15 5 10 38 5 9 F4 10 mM Met, 5.8

[0566] 0.04% (w / v) PS80

[0567] 80 mM Arg. HCl,

[0568] 2 2 2 4 4 2 210 mM Met, 28 10 7 0 38 5 0 F5 5.8 3% w / v sucrose,

[0569] 0.04% (w / v) PS80

[0570] 120 mM Arg. HCl,

[0571] 4 82 12 0 0 19 5 10 9 27 9 15 0 0 F6 10 mM Met, 5.8

[0572] 0.5mg / mL P188

[0573]

[0574] 6% / wv sucrose, F7 o 58.

[0575] 004% ( / )S80 Pwv.

[0576] ©

[0577] cn

[0578] o V)

[0579] (N

[0580] OS

[0581] (N

[0582] v>

[0583] 09 CN

[0584] j-H

[0585]

[0586] Table 13. Size-Exclusion Ultra Performance Liquid Chromatography Results - 40 °C

[0587] TO 40 °C-2 W 40 °C-3 W 40°C-3 M Excipients &

[0588] No. Buffer pH surfactants

[0589] (w / v) Mono HMW LMW Mono HMW LMW Mono HMW LMW Mono HMW LMW mer% % % mer% % % mer% % % mer% % % 120 mM

[0590] Arg. HCl,

[0591] 10 mM Met, 96.0 3.4 0.6 94.8 4.3 1.0 89.5 5.7 4.8 Fl 5.4 98.5 1.4

[0592] 0.05 mM 0.1

[0593] (↓1.5) (↑2.0) (↑0.5) (↓3.7) (↑2.9) (↑0.9) (↓9.0) (↑4.3) (↑4.7) EDTA-2Na,

[0594] 0.04% (w / v)

[0595] PS80

[0596] 120 mM

[0597] Arg. HCl, 91.4 4.7 4.0 10 mM Met, 97.1 2.4 96.4 2.8 0.8

[0598] F2 98.4 1.5 0.1 0.5

[0599] 5.8 0.05 mM (↓1.3) (↑0.9) (↓1.0) (↓1.3) (↑0.7) (↑3.

[0600] EDTA-2Na, (↓1.0) (↑3.2) (↑3.9) 0.04% (w / v)

[0601] PS80

[0602] 20 mM 120 mM

[0603] Histidine Arg. HCl,

[0604] 91.8 4.0 4.2 10 mM Met, 97.1 2.4 96.6 2.6 0.8

[0605] 98.2 1.7 0.1 0.5

[0606] F3 6.2 0.05 mM (↓1.1) (↑0.7) (↓1.6) (↑0.9) (↑0.7) (↓6.4) (↑2.3)

[0607] EDTA-2Na, (↑4.1) 0.04% (w / v)

[0608] PS80

[0609] 120 mM

[0610] 91.0 5.0 4.0 Arg. HCl, 96.9 2.6 96.2 3.0 0.8

[0611] F4 5.8 98.3 1.6 0.1 0.5

[0612] 10 mM Met, (↓1.4) (↑1.0) (↓1.1) (↑1.4) (↑0.7) (↓7.3) (↑3.4) (↑3.9) 0.04% (w / v)

[0613] PS80

[0614] 80 mM 96.8 2.6 96.2 3.0 0.8

[0615] 98.3 1.7 0.1

[0616] F5 0.5 90.7 5.3 4.0

[0617] 5.8 Arg. HCl, (↓1.5) (↑0.9) (↓1.1) (↓1.3) (↑0.7)

[0618] 10 mM Met,

[0619]

[0620] 3% w / v (↓7.6) (↑3.6) (↑3.9) sucrose,

[0621] 0.04% (w / v)

[0622] PS80

[0623] 120 mM

[0624] 5.2 4.2 Arg. HCl, 97.0 2.4 96.4 2.8 0.8 90.6

[0625] 98.4 1.5 0 0.5

[0626] F6 5.8 10 mM Met, (↓1.4) (↑0.9) (↓2.0) (↑1.3) (↑0.8) (↓7.8) (↑4.2)

[0627] 0.5mg / mL P188

[0628] 6% w / v 95.7 3.8 95.2 4.0 0.8 88.6 7.8 3.6 F7 sucrose, 97.9 2.0 0.1 0.5

[0629] 5.8 0.04% (w / v) (↓1.6) (↑1.8) (↓2.7) (↓2.0) (↑0.7) (↓9.3) (↑5.8) (↑3.5)

[0630]

[0631] PS80 Table 14. Size-Exclusion Ultra Performance Liquid Chromatography Results- 25 °C

[0632] TO 25C-2W 25C-3W 25C-3M Excipients &

[0633] No. Buffer pH surfactants Mono HMW LMW Mono HMW LMW Mono HMW LMW Mono HMW LMW (w / v)

[0634] mer % % % mer % % % mer % % % mer % % % 120 mM

[0635] Arg. HCl,

[0636] 97.6

[0637] 10 mM Met,

[0638] 98.5 1.4

[0639] Fl 5.4 0.1 98.5 1.5 0.1 98.4 1.5 0.1 1.8 0.6

[0640] 0.05 mM

[0641] (↓0.9)

[0642] EDTA-2Na,

[0643] 0.04% (w / v)

[0644] PS80

[0645] 120 mM

[0646] Arg. HCl,

[0647] 97.6

[0648] 10 mM Met,

[0649] F2 98.4 1.5 0.1 98.4 1.5 0.1 98.3 1.6 0.1 1.9 0.5

[0650] 5.8 0.05 mM

[0651] EDTA-2Na, (↓0.8)

[0652] 0.04% (w / v)

[0653] PS80

[0654] 20 mM 120 mM

[0655] Histidine Arg. HCl,

[0656] 97.4

[0657] 10 mM Met,

[0658] 98.2 98.2 2.1

[0659] F3 6.2 1.7 0.1 98.3 1.7 0.1 1.7 0.1 0.5

[0660] 0.05 mM

[0661] EDTA-2Na, (↓0.8)

[0662] 0.04% (w / v)

[0663] PS80

[0664] 120mM

[0665] 97.6

[0666] Arg. HCl,

[0667] F4 0.

[0668] 5.8 98.3 1.6 0.1 98.3 1.6 0.1 98.3 1.6 0.1 2.0 4 10 mM Met,

[0669] 0.04% (w / v) (↓0.7)

[0670] PS80

[0671] 97.4

[0672] 80 mM

[0673] 98.3 1.7 0.1 98.3 1.6 0.1 98.2 1.7 0.1 2.1 0.5 F5 5.8 Arg. HCl,

[0674] (↓0.9)

[0675] 10 mM Met,

[0676]

[0677] 3% w / v

[0678] sucrose,

[0679] 0.04% (w / v)

[0680] PS80

[0681] 120 mM

[0682] 97.7

[0683] Arg. HCl, 98.4 1.5 0.0 98.4 1.5 0.1 98.3 1.6 0.1 1.9 0.5 F6 5.8 10 mM Met,

[0684] 0.5mg / mL (↓0.7)

[0685] P188

[0686] 6% w / v 96.5 3.0

[0687] F7 sucrose, 97.9 2.0 0.1 97.8 2.1 0.1 97.7 2.2 0.1 0.5

[0688] 5.8 0.04% (w / v) (↓1.4) (↑1.0)

[0689]

[0690] PS80 Table 15. Size-Exclusion Ultra Performance Liquid Chromatography Results- 5 °C

[0691] TO 5C-2W 5C-3W 5C-3M Excipients &

[0692] No. Buffer pH surfactants

[0693] (w / v) Mono HMW LMW Mono HMW LMW Mono HMW LMW Mono HMW LMW mer % % % mer % % % mer % % % mer % % % 120mM

[0694] Arg. HCl,

[0695] 10 mM Met,

[0696] Fl 1.4 1.

[0697] 5.4 98.5 0.1 98.7 1.3 0.1 98.6 1.3 0.1 98.5 4 0.1 0.05 mM

[0698] EDTA-2Na,

[0699] 0.04% (w / v)

[0700] PS80

[0701] 120mM

[0702] Arg. HCl,

[0703] 10 mM Met,

[0704] F2 98.4 1.5 0.1 98.5 1.4 0.1 98.5 1.4 0.1 98.3 1.5 0.1

[0705] 5.8 0.05 mM

[0706] EDTA-2Na,

[0707] 0.04% (w / v)

[0708] PS80

[0709] 20 mM 120mM

[0710] Histidine Arg. HCl,

[0711] 10 mM Met,

[0712] 98.2 98.2

[0713] F3 6.2 1.7 0.1 98.3 1.6 0.1 98.3 1.6 0.1 1.7 0.1

[0714] 0.05 mM

[0715] EDTA-2Na,

[0716] 0.04% (w / v)

[0717] PS80

[0718] 120mM

[0719] Arg. HCl,

[0720] 1.4 1.4

[0721] F4 98.3 1.6 0.1 98.5 0.0 98.5 0.0 98.3 1.6 0.1

[0722] 5.8 10 mM Met,

[0723] 0.04% (w / v)

[0724] PS80

[0725] 80 mM

[0726] 98.3 1.7 0.1 98.4 1.5 0.1 98.4 1.5 0.1 98.3 1.6 0.1 F5 5.8 Arg. HCl,

[0727]

[0728] 10 mM Met, 3% w / v

[0729] sucrose,

[0730] 0.04% (w / v)

[0731] PS80

[0732] 120mM

[0733] Arg. HCl, 98.4 1.5 0.0 98.6 1.4 0.1 98.6 1.4 0.1 98.4 1.5 0.1 F6 5.8 10 mM Met,

[0734] 0.5mg / mL

[0735] P188

[0736] 6% w / v

[0737] F7 sucrose, 97.9 2.0 0.1 98.0 1.9 0.1 98.0 1.9 0.1 97.8 2.1 0.1

[0738] 5.8 0.04% (w / v)

[0739]

[0740] PS80 Table 16. CE-SDS Caliper-NR Results

[0741] Caliper-NR (Purity %)

[0742] Excipients &

[0743] No. Buffer pH surfactants

[0744] (w / v) 40C- 40C- 25C- 25C- 25C- 5C- 5C- 5C- FT-5

[0745] TO 40C-3M A-3D

[0746] 2W 3W 2W 3W 3M 2W 3W 3M cycles 120mM

[0747] Arg. HCl, 85.4

[0748] 10 mM Met, 94.3

[0749] F1 5.4 0.05 mM 96.9 95.1 97.1 96.9 95.8 97.0 96.9 96.8 96.8 97.1

[0750] (↓2.6) (↓11.5)

[0751] EDTA-2Na,

[0752] 0.04% (w / v)

[0753] PS80

[0754] 120mM

[0755] Arg. HCl,

[0756] 86.7

[0757] 10 mM Met, 94.6

[0758] F2 96.7 95.4 97.1 97.0 95.8 97.2 97.2 96.9 96.8 97.1

[0759] 5.8 0.05 mM (↓2.1)

[0760] EDTA'2Na, (↓10.0)

[0761] 0.04% (w / v)

[0762] PS80

[0763] 20 mM 120mM

[0764] Histidine Arg. HCl,

[0765] 86.3

[0766] 10 mM Met, 94.5

[0767] F3 6.2 96.8 95.5 97.0 96.9 95.5 97.3 97.1 96.8 96.9 96.9

[0768] 0.05 mM (↓12.3) (↓10.5)

[0769] EDTA-2Na,

[0770] 0.04% (w / v)

[0771] PS80

[0772] 120mM

[0773] 85.6

[0774] Arg. HCl, 94.3

[0775] F4 96.8 95.3 96.9 96.8 95.5 97.4 97.2

[0776] 5.8 96.7 97.2 96.8 10 mM Met, (↓2.5) (↓11.2)

[0777] 0.04% (w / v)

[0778] PS80

[0779] 80 mM 94.5

[0780] 96.9 95.2

[0781] F5 85.8 97.3 96.7 95.9 97.3 97.3 97.0 97.0 97.0

[0782] 5.8 Arg. HCl, (↓2.4)

[0783]

[0784] 10 mM Met, 3% w / v (↓11.1)

[0785] sucrose, 0.04%

[0786] (w / v) PS80

[0787] 120mM 94.3 85.2

[0788] Arg. HCl, 96.9 95.3 96.9 96.9 95.9 97.3 97.0 96.5 97.2 97.0 F6 5.8

[0789] 10 mM Met, (↓2.6) (↓11.7)

[0790] 0.5mg / mL P188

[0791] 85.2 94.5

[0792] 6% w / v 93.8

[0793] 96.8 94.8 97.0 96.7 97.0 97.0 96.6 97.2 96.9 F7 5.8 sucrose, 0.04% (↓3.0) (↓11.6)

[0794] (w / v) PS80 (↓2.3)

[0795]

[0796]

[0797]

[0798] W - weeks, M - months, A - agitation, D - day,

[0799]

[0800] - freeze and thaw, NR - non-reduced Table 17. CE-SDS Caliper-R Results

[0801] Caliper-R, LC+HC,%, (A%)

[0802] No. Buffer Excipients &

[0803] pH surfactants (w / v) 40C- 40C- 40C- 25C- 25C- 25C- FT-5

[0804] TO 5C-3M A-3D 5C-2W 5C-3W

[0805] 2W 3W 3M 2W 3W 3M cycles 120mM Arg. HCl, 94.7

[0806] 10 mM Met,

[0807] 99.4 99.2 98.9 99.5 99.5 98.7 99.5 99.4 99.2

[0808] F1 5.4 99.7 99.5

[0809] 0.05 mM

[0810] (↓4.7)

[0811] EDTA-2Na,

[0812] 0.04% (w / v) PS80

[0813] 120mM Arg. HCl, 95.4

[0814] 10 mM Met,

[0815] 99.4 99.2 99.4 99.4 98.9 98.7 99.5 99.5 99.1 99.7 99.5 F2 0.05 mM 5.8 (↓4.0)

[0816] EDTA-2Na,

[0817] 0.04% (w / v) PS80

[0818] 120mM Arg. HCl, 94.9

[0819] 10 mM Met,

[0820] 99.4 99.4 99.4 99.1 99.1 99.3 98.8 99.5 99.3 99.7 99.7 0.05 mM 6.2 F3 (↓4.5) 20 mM EDTA-2Na,

[0821] Histidine 0.04% (w / v) PS80

[0822] 95.7

[0823] 120mM Arg. HCl,

[0824] 99.4 99.2 99.4 99.4 99.2 99.4 98.9 99.5 98.7 99.5 99.5 F4 5.8 10 mM Met,

[0825] (↓3.7)

[0826] 0.04% (w / v) PS80

[0827] 96.1 80 mM Arg. HCl,

[0828] 99.4 99.4 99.410 mM Met, 99.0 98.8 99.5 98.8 99.5 99.3 99.5 99.5 F5 5.8 3% w / v sucrose, (↓3.3)

[0829] 0.04% (w / v) PS80

[0830] 94.7

[0831] 120mM Arg. HCl,

[0832] 99.4 99.3 99.3 99.0 99.5 98.7 99.5 99.5 99.3 99.5 99.6 F6 10 mM Met, 5.8 (↓4.6)

[0833] 0.5mg / mL P188

[0834]

[0835] 94.8

[0836] 6% w / v sucrose, 99.4 99.1 98.8 99.5 99.3 98.4 99.4 99.4 99.3 99.5 99.7 F7 5.8

[0837] 0.04% (w / v) PS80 (↓4.6)

[0838]

[0839] W = weeks, M = months, A = agitation, D = day, FT = freeze and thaw, R = reduced, LC = light chain, HC = heavy chain Table 18 sets forth the imaged capillary isoelectric focusing (icIEF) results for Formulations Fl through F7 at 40 °C through 3 months. After incubation at 40 °C for 3 months, 34.1-36.6% main peak % decreases were observed in all formulations. No substantial differences were observed among all 7 formulations.

[0840] Table 19 sets forth the icIEF results for Formulations Fl through F7 at 25 °C through 3 months. After incubation at 25 °C for 3 months, 3.3-7.6% main peak % decreases were observed. No substantial changes were observed in all formulations. F7 had highest decrease of main peak % among all formulations.

[0841] Table 20 sets forth the icIEF results for Formulations Fl through F7 at 5 °C through 3 months. After incubation at 5 °C for 3 months, no substantial changes were observed in all formulations. No substantial differences were observed among all 7 formulations.

[0842] Table 21 sets forth the PS80 / P188 results for Formulations Fl through F7. No substantial decrease was observed in EDTA containing formulations (F1-F3) after 3 months incubation at 5 °C, 25 °C, or 40 °C compared with TO. For F4, F5, F7 without EDTA, a substantial decrease was observed after 3 months incubation at 25 °C or 40 °C while no change was observed after 3 months incubation at 5 °C compared with TO. It is noted that the TO and 3W samples of F6 were tested at a different lab from the 3 month samples of F6 and thus results might not be comparable.

[0843] Table 22 sets forth the potency results for Formulations F2 and F3. There were no substantial changes of potency % after 3 months of incubation at 5 °C, 25 °C, and 40 °C for F2 and F3.

[0844] Table 23 sets forth the osmolality, viscosity, and pH results for Formulations Fl through F7. The pH values are close to the target value. All formulations were within the isotonic range, and the viscosity value was from 5.0-6.2.

[0845] Table 24 sets forth the sub-visible particles results for Formulations Fl through F7 after agitation for 3 days (A-3D) and freeze / thaw for 5 cycles (FT-5 Cycles). No substantial changes of sub-visible particles were observed in all formulations after A-3D and freeze / thaw for 5 cycles.

[0846] Table 25 sets forth the SE-UPLC results for Formulations Fl through F7 after A- 3D and freeze / thaw for 5 cycles. No substantial changes of SE-UPLC monomer % were observed in all formulations after freeze / thaw for 5 cycles and A-3D.

[0847] Table 26 sets forth the icIEF results for Formulations Fl through F7 after A-3D and freeze / thaw for 5 cycles. No substantial changes were observed in all formulations after FT-5 cycles and A- 3D. No substantial differences were observed among all 7 formulations. Table 18. icIEF Results - 40 °C

[0848] iCIEF

[0849] Excipients & TO 40C-2W 40C-3W 40C-3M No. Buffer pH

[0850] surfactants (w / v)

[0851] AP% MP% BP% AP% MP% BP% AP% MP% BP% AP% MP% BP% 120mM Arg. HCl, 28.4 61.6 32.5 56.7 10.8 51.7 34.6 13.7 10 mM Met, 21.6 71.0 7.4 10.0

[0852] F1 5.4 0.05 mM EDTA-2Na, (↑6.8) (↑9.4) (↑10.9) (↑14.3) (↑3.4) (↑30.1) (↑36.4) (↑6.3)

[0853] 0.04% (w / v) PS80

[0854] 120mM Arg. HCl, 28.2 62.3 32.0 58.0 55.3 35.6 10 mM Met, 21.7 70.9 7.4 9.6 10.0 9.1 F2 5.8 0.05 mM EDTA-2Na, (↑6.5) (↑8.6) (↑10.3) (↑12.9) (↑33.6) (↑35.3)

[0855] 0.04% (w / v) PS80

[0856] 120mM Arg. HCl, 27.5 63.0 30.2 59.9 55.0 36.1 10 mM Met, 22.1 70.6 7.3 9.5 9.9 8.9 F3 6.2

[0857] 0.05 mM EDTA-2Na, (↑5.4) (↑7.6) (↑8.1) (↑10.7) (↑32.9) (↑34.5) 0.04% (w / v) PS80

[0858] 20 mM 120mM Arg. HCl, 29.1 61.5 31.7 58.4 59.3 31.2

[0859] 21.7 71.1 7.3 9.4 9.8 9.5 F4 Histidine 5.8 10 mM Met, (↑7.4) (↑9.6) (↑10.0) (↑12.7) (↑37.6) (↑39.9)

[0860] 0.04% (w / v) PS80

[0861] 80 mM Arg. HCl, 29.3 61.2 32.4 57.8 55.5 37.0 10 mM Met, 21.6 71.1 7.3 9.6 9.8 7.5 F5 5.8 3% w / v sucrose, (↑7.7) (↑9.9) (↑10.8) (↑13.9) (↑33.9) (↑34.1)

[0862] 0.04% (w / v) PS80

[0863] 120mM Arg. HCl, 28.0 62.7 32.3 57.7 57.3 34.8

[0864] 21.4 71.2 7.4 9.3 10.0 7.9 F6 5.8 10 mM Met, (↑6.6) (↑8.5) (↑10.9) (↑13.5) (↑35.9) (↑36.4)

[0865] 0.5mg / mL P188

[0866] 32.0 59.1 36.7 54.0 61.0 34.2 6% w / v sucrose, 21.8 70.8 7.4 9.0 9.3 4.7 F7 5.8 0.04% (w / v) PS80 (↑10.2) (↑11.7) (↑14.9) (↑16.8) (↑39.2) (↑36.6)

[0867]

[0868] AP = Acidic peak, MP = main peak, BP = basic peak, W = weeks, M = months Table 19. icIEF Results - 25 °C

[0869] iCIEF

[0870] Excipients & TO 25C-3M No. Buffer 25C-2W 25C-3W

[0871] pH surfactants (w / v)

[0872] AP% MP% BP% AP% MP% BP% AP% MP% BP% AP% MP% BP% 120mM Arg. HCl, 25.9 65.4 10 mM Met, 21.6 71.0 7.4 22.1 70.4 7.6 22.8 69.3 8.0 8.8 Fl 5.4 0.05 mM EDTA-2Na, (↑4.3) (↑5.6)

[0873] 0.04% (w / v) PS80

[0874] 120mM Arg. HCl, 25.3 66.5 10 mM Met, 21.7 70.9 7.4 22.5 70.0 7.5 22.9 69.5 7.6 8.2 F2 5.8 0.05 mM EDTA-2Na, (↑3.6) (↑4.4)

[0875] 0.04% (w / v) PS80

[0876] 120mM Arg. HCl, 67.3 10 mM Met, 22.1 70.6 7.3 22.2 70.1 7.7 22.4 69.6 7.6 25.0 7.8 F3 6.2

[0877] 0.05 mM EDTA-2Na, (↑3.3) 0.04% (w / v) PS80

[0878] 20 mM 120mM Arg. HCl, 25.4 66.6

[0879] 21.7 71.1 7.3 22.7 69.7 7.6 22.8 69.5 7.7 8.0 F4 Histidine 5.8 10 mM Met, (↑3.7) (↑4.5)

[0880] 0.04% (w / v) PS80

[0881] 80 mM Arg. HCl, 25.6 66.3 10 mM Met, 21.6 71.1 7.3 22.8 69.7 7.6 23.0 69.3 7.7 8.1 F5 5.8 3% w / v sucrose, (↑4.0) (↑4.8)

[0882] 0.04% (w / v) PS80

[0883] 120mM Arg. HCl, 25.0 66.8

[0884] 21.4 71.2 7.4

[0885] 5.8 22.6 77.0 7.5 22.6 69.8 7.7 8.2 F6 10 mM Met, (↑3.6) (↑4.4)

[0886] 0.5mg / mL P188

[0887] 29.2 63.2 6% w / v sucrose, 21.8 70.8 7.4 22.7 69.7 7.6 23.7 68.6 7.7 7.7 F7 5.8 0.04% (w / v) PS80 (↑7.4) (↑7.6)

[0888]

[0889] AP = Acidic peak, MP = main peak, BP = basic peak, W = weeks, M = months Table 20. icIEF Results - 5 °C

[0890] iCIEF

[0891] No. Buffer Excipients & TO 5C-2W 5C-3W 5C-3M pH surfactants (w / v)

[0892] AP% MP% BP% AP% MP% BP% AP% MP% BP% AP% MP% BP% 120 mM Arg. HCl,

[0893] Fl 5.4 10 mM Met, 21.6 71.0 7.4 21.6 71.1 7.3 21.9 71.0 7.1 21.4 71.7 6.9

[0894] 0.05 mM EDTA-2Na,

[0895] 0.04% (w / v) PS80

[0896] 120 mM Arg. HCl,

[0897] F2 5.8 10 mM Met, 21.7 70.9 7.4 22.0 70.8 7.2 22.0 70.8 7.2 20.8 71.6 7.5

[0898] 0.05 mM EDTA'2Na,

[0899] 0.04% (w / v) PS80

[0900] 120 mM Arg. HCl,

[0901] F3 6.2 10 mM Met, 22.1 70.6 7.3 21.7 71.0 7.3 22.0 70.9 7.1 21.2 72.1 6.8

[0902] 0.05 mM EDTA'2Na,

[0903] 20 mM 0.04% (w / v) PS80

[0904] Histidine 120 mM Arg. HCl,

[0905] F4 21.7 71.1 7.3 21.7 71.0 7.4 21.9 71.0 7.2 20.2

[0906] 5.8 72.8 7.0 10 mM Met,

[0907] 0.04% (w / v) PS80

[0908] 80 mM Arg. HCl,

[0909] F5 5.8 10 mM Met, 21.6 71.1 7.3 22.2 70.6 7.3 22.1 70.7 7.2 20.5 72.4 7.1

[0910] 3% w / v sucrose,

[0911] 0.04% (w / v) PS80

[0912] 120 mM Arg. HCl,

[0913] 21.4 71.2 7.4 7.2 22.1 7.2 72.2 F6 5.8 22.3 70.5 70.7 21.0 6.9

[0914] 10 mM Met,

[0915] 0.5 mg / mL P188

[0916] F7 5.8 6% w / v sucrose, 21.8 70.8 7.4 22.0 70.7 7.3 22.2 70.5 7.3 21.6 71.4 7.0

[0917]

[0918] 0.04% (w / v) w / v PS80

[0919] AP - Acidic peak, MP - main peak, BP - basic peak, W - weeks, M - months Table 21. PS80 / P188 Results

[0920] Buffer PS80 / P188 concentration (%)

[0921] Excipients &

[0922] No. pH

[0923] surfactants (w / v)

[0924] TO 40C-3W 40C-3M 25C-3W 25C-3M 5C-3W 5C-3M 120 mM Arg. HCl,

[0925] 10 mM Met,

[0926] Fl 5.4 0.035 0.035 0.032 0.033 0.034 0.034 0.035

[0927] 0.05 mM EDTA-2Na,

[0928] 0.04% (w / v) PS80

[0929] 120 mM Arg. HCl,

[0930] 10 mM Met,

[0931] F2 5.8 0.035 0.033 0.030 0.031 0.032 0.034 0.033

[0932] 0.05 mM EDTA-2Na,

[0933] 0.04% (w / v) PS80

[0934] 120 mM Arg. HCl,

[0935] 10 mM Met,

[0936] F3 6.2 0.035 0.041 0.036 0.041 0.038 0.034 0.040

[0937] 20 mM 0.05 mM EDTA-2Na,

[0938] Histidine 0.04% (w / v) PS80

[0939] 120 mM Arg. HCl,

[0940] 0.013 0.024 0.014

[0941] F4 5.8 10 mM Met, 0.040 ND 0.033 0.033

[0942] (↓0.027) (↓0.016) (↓0.026)

[0943] 0.04% (w / v) PS80

[0944] 80 mM Arg. HCl,

[0945] 10 mM Met, 0.015 0.015

[0946] F5 5.8 0.036 <0.0050 0.028 0.035 0.037

[0947] 3% w / v sucrose, (↓0.021) (↓0.021)

[0948] 0.04% (w / v) PS80

[0949] 120 mM Arg. HCl,

[0950] F6 5.8 10 mM Met, 0.071* 0.062 0.050 0.064 0.049 0.068 0.051

[0951] 0.5mg / mL P188

[0952] 6% w / v sucrose, 0.004 0.021 0.015

[0953] F7 5.8 0.033 <0.0050 0.037 0.032

[0954]

[0955] 0.04% (w / v) PS80 (↓0.029) (↓0.012) (↓0.018)

[0956] *T0 and 3W samples of F6 were tested at a different lab from the 3 month samples of F6 and thus results might not be comparable. Table 22. Potency Results

[0957] Potency (%)

[0958] No. Formulations

[0959] TO 40°C-3 W 40°C-3 M 25°C-3 M 5°C-3 M 20mM His.,120mM Arg-HCl, lOmM Methionine,

[0960] F2 100 100 90 93 101 0.05 mM EDTA.2Na, 0.04% (w / v) PS80, pH 5.8

[0961] 20mM His.,120mM Arg-HCl, lOmM Methionine,

[0962] F3 104 100 86 95 98 0.05 mM EDTA.2Na, 0.04% (w / v) PS80, pH 6.2

[0963]

[0964] Table 23. Osmolality, Viscosity, and pH Results

[0965] Osmolality Viscosity Formulation pH

[0966] (mOsmol / kg) (mPa-s, 20 °C) No.

[0967] Buffer pH Excipients & surfactants (w / v) TO

[0968] 120mM Arg. HCl, 10 mM Met, 0.05 mM EDTA-2Na, 0.04%

[0969] Fl 5.4 5.3 314 5.2 (w / v) PS80

[0970] 120mM Arg. HCl, 10 mM Met, 0.05 mM EDTA-2Na, 0.04%

[0971] F2 5.8 5.7 295 5.0 (w / v) PS80

[0972] 120mM Arg. HCl, 10 mM Met, 0.05 mM EDTA-2Na, 0.04%

[0973] F3 6.2 6.1 307 5.2 (w / v) PS80

[0974] 20 mM

[0975] F4 5.8 120mM Arg. HCl, 10 mM Met, 0.04% (w / v) PS80 5.8 311 5.2 Histidine

[0976] 80 mM Arg. HCl, 10 mM Met, 3% w / v sucrose, 0.04% (w / v)

[0977] F5 5.8 5.7 356 5.4 PS80

[0978] F6 5.8 120mM Arg. HCl, 10 mM Met, 0.5mg / mL P188 5.7 309 5.2 F7 5.8 6% w / v sucrose, 0.04% (w / v) PS80 5.7 297 6.2

[0979]

[0980] Table 24. Sub-visible Partides Results

[0981] Sub-visible partides

[0982] No. TO A-3D FT -5 Cycles

[0983] >2 pm > 10 pm >25 pm > 2 pm > 10 pm >25 pm > 2 pm > 10 pm >25 pm Fl

[0984] 281 25 4 254 12 0 264 28 9 F2

[0985] 91 14 4 138 17 5 253 20 4 F3 141 19 9 77 5 0 412 43 10 F4

[0986] 228 23 5 251 25 2 1024 66 0 F5 130 28 2 177 12 0 200 5 2 F6

[0987] 53 0 0 397 38 4 287 40 9 F7

[0988] 100 14 2 51 2 2 435 35 0

[0989]

[0990] Table 25. SE-UPLC Results

[0991] SEC-UPLC

[0992] No. TO A-3D FT-5 Cycles Monomer % HMW% LMW% Monomer% HMW% LMW% Monomer % HMW% LMW%

[0993] Fl

[0994] 98.5 1.4 0.1 98.6 1.3 0.1 98.6 1.4 0.0 F2

[0995] 98.4 1.5 0.1 98.5 1.4 0.1 98.5 1.5 0.1 F3

[0996] 98.2 1.7 0.1 98.4 1.6 0.1 98.3 1.6 0.1 F4

[0997] 98.3 1.6 0.1 98.5 1.4 0.1 98.4 1.5 0.1 F5

[0998] 98.3 1.7 0.1 98.4 1.5 0.1 98.4 1.6 0.1 F6

[0999] 98.4 1.5 0.0 98.6 1.4 0.1 98.5 1.4 0.1 F7

[1000] 97.9 2.0 0.1 98.0 1.9 0.1 98.0 1.9 0.1

[1001]

[1002] Table 26. icIEF Results - A-3D and FT-5 Cydes

[1003] iCIEF

[1004] No. TO A-3 D FT-5 C AP% MP% BP% AP% MP% BP% AP% MP% BP% Fl

[1005] 21.6 71.0 7.4 21.9 70.9 7.3 21.8 70.9 7.4 F2

[1006] 21.7 70.9 7.4 22.2 70.6 7.2 22.2 70.5 7.3 F3 22.1 70.6 7.3 22.4 70.3 7.3 21.9 71.0 7.2 F4

[1007] 21.7 71.1 7.3 21.9 70.8 7.3 21.9 71.1 7.0 F5

[1008] 21.6 71.1 7.3 22.1 70.5 7.4 22.2 70.4 7.4 F6

[1009] 21.4 71.2 7.4 21.7 70.9 7.4 22.1 70.6 7.3 F7

[1010] 21.8 70.8 7.4 22.0 70.5 7.5 22.4 70.2 7.4

[1011]

[1012] AP = Acidic peak, MP = main peak, BP = basic peak, A = agitation, D = day, FT = freeze and thaw, C = cycles Table 27 is a summary chart that ranks Formulations Fl through F7 by performance. One star denotes poor performance, two stars denotes good performance, and three stars denotes excellent performance. This screening study showed that Construct 114 is compatible with L-histidine, L-histidine-HCl, L-arginine-HCl, L-methionine, EDTA-2Na and polysorbate 80 or poloxamer 188 at pH values ranging from 5.4 to 6.2. Both the F2 and F3 formulations were suitable based on stability results. Incorporating these findings, and to preserve flexibility in potentially formulating Construct 114 with other agents, it was decided to proceed with further study of a formulation comprising 10 mM histidine buffer (10 mM L-histidine / L-histidine-HCl), 120 mM Arg-HCl, 10 mM Methionine (e.g., L-methionine), 0.05 mM EDTA-2Na, and 0.05% (w / v) PS80, at pH 6.0. Table 27. Summary of Formulations F1-F7

[1013] No. Buffer pH Excipients & Appearance MFI SE-UPLC Caliper-NR Caliper-R iCIEF PS80 / P188 surfactants (w / v)

[1014] Fl 20 mM 5.4 120 mM Arg. HCl, ★★★ ★★★ ★★ ★★★ ★★★ ★★★ ★★★ Histidine 10 mM Met,

[1015] 0.05 mM EDTA-2Na,

[1016] 0.04% (w / v) PS80

[1017] F2 5.8 120 mM Arg. HCl, ★★★ ★ ★★ ★ ★★ ★ ★★ ★★★ ★ ★★ ★ ★★

[1018] 10 mM Met,

[1019] 0.05 mM EDTA'2Na,

[1020] 0.04% (w / v) PS80

[1021] F3 6.2 120 mM Arg. HCl, ★★★ ★ ★★ ★ ★★ ★★★ ★★★ ★ ★★ ★★★

[1022] 10 mM Met,

[1023] 0.05 mM EDTA-2Na,

[1024] 0.04% (w / v) PS80

[1025] F4 5.8 120 mM Arg. HCl, ★★★ ★ ★★ ★ ★★ ★★★ ★★★ ★ ★★ ★ ★

[1026] 10 mM Met,

[1027] 0.04% (w / v) PS80

[1028] F5 5.8 80 mM Arg. HCl, ★★★ ★ ★★ ★ ★★ ★★★ ★★★ ★ ★★ ★ ★

[1029] 10 mM Met,

[1030] 3% w / v sucrose,

[1031] 0.04% (w / v) PS80

[1032] F6 5.8 120 mM Arg. HCl, ★★★ ★★★ ★ ★★ ★★★ ★★★ ★★★ ★

[1033] 10 mM Met,

[1034] 0.5 mg / mLP188

[1035] F7 5.8 6% w / v sucrose, ★★★ ★ ★★ ★ ★ ★ ★ ★ ★★ ★ ★ ★ ★

[1036] 0.04% (w / v) PS80

[1037]

[1038] Performance ranking: ★ Poor ★★ Good ★★★ Excellent Example 2: Evaluation of high concentration formulations of Construct 114 in pre-filled syringes

[1039] A study was performed to evaluate the stability of formulations containing 180 mg / mL, 200 mg / mL or 220 mg / mL of Construct 114, 10 mM L-histidine / L-histidine HC1, 120 mM L-arginine HC1, 10 mM L-methionine, 0.05 mM EDTA, and 0.05% (w / v) polysorbate 80, at pH 6.0. Formulations were stored in pre-filled syringes at 5 °C and 25 °C for 1 month, 3 months, and 6 months and at 40 °C for half a month, 1 month, and 3 months. Stability was analyzed using appearance, SEC, CE-SDS (R& NR), iCIEF, ELISA, MFI, and SoloVPE, and measurements of pH, osmolality, viscosity, and PS80. Data are provided in Tables 28-30.

[1040] Minimal changes were observed using SEC for all three formulations tested for samples stored at 5 °C for IM, 3M, and 6M and only slight changes were seen in %HMW and %LMW in samples stored at 25 °C. There were also minimal changes in > 10 pm sub-visible particles after 6 months of storage at 5 °C for all tested formulations, though an increase in > 10 pm sub-visible particles was observed after 6 months of storage at 25 °C for all Construct 114 concentrations. In addition, no changes in potency as assessed by ELISA were observed after 6 months of storage at 5 °C or 25 °C.

[1041] Overall, the stability parameters for formulations containing 180 mg / mL, 200 mg / mL, or 220 mg / mL Construct 114 showed minimal changes in visual appearance, turbidity, concentration, sub-visible particles, PS80, pH, viscosity, SEC, icIEF, and ELISA after 6 months of storage at 5 °C or 25 °C. Table 28. Stability Results for Formulation Containing 180 mg / mL Construct 114

[1042] 180 mg / mL Construct 114 5 °C 25 °C 40 °C

[1043] TO IM 3M 6M IM 3M 6M 0.5M IM 3M Appearance SY, SY, SY, SY, SY, SY, SY, SY, SY, SY,

[1044] SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP Concentration (mg / mL) 178.1 176.2 175.9 177.2 176.9 175.1 174.3 179 180.2 176.8 Turbidity 0.11 0.11 0.11 0.1 0.11 0.12 0.12 0.12 0.13 0.15 Osmolality (mOsm / kg) 303 NT NT NT NT NT 304 NT NT NT PH 6.0 NT NT NT NT NT NT NT NT NT PS80 (% w / v) 0.082 0.056 NT 0.057 0.068 NT 0.051 NT 0.071 NT SVP by MFI, > 2 pm 17421 3214 5982 4124 6120 22547 76066 13262 69862 141483 particles / mL > 10 pm 514 67 149 192 115 452 3354 261 2353 5200

[1045] > 25 pm 83 0 2 18 5 13 28 25 21 347 SEC-UPLC %Monomer 98.4 98.4 98.4 98.3 98.0 97.7 97.0 97.0 96.3 94.0

[1046] %HMW 1.4 1.5 1.4 1.6 1.7 1.9 2.4 2.5 3.1 4.3 %LMW 0.1 0.2 0.1 0.1 0.3 0.4 0.7 0.5 0.7 1.7 CE-SDS NR %Purity 95.5 NT 94.8 94.7 NT 90.6 91.9 NT 92.0 87.1

[1047] %LMW 4.0 NT 4.3 4.0 NT 5.7 6.4 NT 2.8 10.6 %HMW 0.5 NT 0.9 1.3 NT 3.7 1.7 NT 0.7 2.2 CE-SDS R %LC+HC 97.3 NT 97.3 97.0 NT 97.1 95.7 NT 95.4 93.4

[1048] %LMW 1.4 NT 1.2 1.2 NT 0.7 2.1 NT 2.4 2.2 %HMW 1.3 NT 1.5 1.7 NT 1.5 2.3 NT 2.2 3.3 iCIEF %MP 64.8 NT 62.1 58.3 58.3 56.5 49.4 54.7 48.9 33.4

[1049] %AP 26.6 NT 27.2 32.5 32.9 31.1 36.5 35.3 40.9 53.4

[1050]

[1051] %BP 8.6 NT 10.7 9.2 8.8 12.4 13.8 10.0 10.2 13.2 ELISA Construct 114 89 90 NT 92 104 NT 96 101 92 NT

[1052]

[1053] Potency%

[1054] SY = Slightly yellow; SO = Slightly opalescent Equid; EFP = essentially free of visible particles; AP = Acidic peak; MP = main peak; BP = basic peak; M = months; LC = light chain; HC = heavy chain; LMW = low molecular weight; HMW = high molecular weight; NT = not tested Table 29. Stability Results for Formulation Containing 200 mg / mL Construct 114

[1055] 200 mg / mL Construct 5 °C 25 °C 40 °C

[1056] 114 TO IM 3M 6M IM 3M 6M 0.5M IM 3M Appearance SY, SY, SY, SY, SY, SY, SY, SY, SY, SY,

[1057] SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP Concentration (mg / mL) 199.1 200.4 198.1 201.9 199.8 197.9 200.7 199.7 201.9 200.0 Turbidity 0.12 0.12 0.11 0.11 0.12 0.13 0.13 0.13 0.14 0.16 Osmolality (mOsm / kg) 305 NT NT NT NT NT 299 NT NT NT pH 6.1 NT NT NT NT NT NT NT NT NT PS80 (% w / v) 0.074 0.071 NT 0.071 0.053 NT 0.064 NT NT SVP by > 2 pm 5227 7888 2610 2001 6748 56959 182611 9517 26290 91629 MFI, ≥ 10 μm 280 280 344 174 239 1519 15297 252 1449 12139 particles / mL > 25 pm 39 8 97 20 10 52 83 28 36 385 SEC-UPLC %Monomer 98.3 98.3 98.3 98.1 97.8 97.4 96.6 96.8 95.9 93.4

[1058] %HMW 1.6 1.6 1.6 1.8 1.9 2.2 2.7 2.8 3.4 4.9 %LMW 0.1 0.1 0.1 0.1 0.3 0.4 0.7 0.5 0.7 1.7 CE-SDS %Purity 94.4 NT 94.2 94.6 NT 92.9 91.3 NT 91.4 86.5 NR %LMW 4.9 NT 4.6 4.3 NT 5.8 6.8 NT 6.8 10.9

[1059] %HMW 0.6 NT 1.2 1.1 NT 1.3 1.9 NT 1.7 2.6 CE-SDS R %LC+HC 97.4 NT 97.2 97.1 NT 96.1 96.0 NT 95.2 93.6

[1060] %LMW 1.3 NT 1.2 1.4 NT 0.8 1.9 NT 2.3 2.4 %HMW 1.4 NT 1.6 1.6 NT 2.3 2.1 NT 2.5 2.9 iCIEF %MP 63.3 60.1 61.4 61.7 58.6 56.3 50.1 54.9 48.8 34.4

[1061] %AP 27.9 31.6 28.0 25.6 33.5 31.4 36.5 35.4 41.1 52.0

[1062]

[1063] %BP 8.8 8.3 10.6 12.7 8.1 12.3 13.4 9.8 10.1 13.6 ELISA Construct 114 98 94 NT 98 103 NT 99 118 100 NT

[1064]

[1065] Potency%

[1066] SY = Slightly yellow; SO = Slightly opalescent liquid; EFP = essentially free of visible particles; AP = Acidic peak; MP = main peak; BP = basic peak; M = months; LC = light chain; HC = heavy chain; LMW = low molecular weight; BMW = high molecular weight; NT = not tested Table 30. Stability Results for Formulation Containing 220 mg / mL Construct 114

[1067] 220 mg / mL Construct 5 °C 25 °C 40 °C

[1068] 114 TO IM 3M 6M IM 3M 6M 0.5M IM 3M Appearance SY, SY, SY, SY, SY, SY, SY, SY, SY, SY,

[1069] SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP Concentration (mg / mL) 219.8 218.3 217.4 215.3 222 217.7 217.8 219.2 223.9 218.8 Turbidity 0.12 0.12 0.12 0.12 0.13 0.13 0.15 0.14 0.14 0.17 Osmolality (mOsm / kg) 314 NT NT NT NT NT 308 NT NT NT PH 6.1 NT NT NT NT NT NT NT NT NT PS80 (% w / v) 0.065 0.069 NT 0.073 NT 0.062 NT NT SVP by > 2 pm 3541 4545 1549 1367 5254 15672 63776 9079 13298 41901 MFI, > 10 pm 246 174 139 95 216 2361 9289 502 1107 8315 particles / > 25 pm 64 39 26 25 7 175 102 37 74 442 mL

[1070] SEC- %Monomer 98.2 98.2 98.2 98.0 97.7 97.4 96.4 96.5 95.6 93.4 UPLC %HMW 1.6 1.7 1.6 1.9 2.1 2.3 2.9 3.0 3.7 5.1

[1071] %LMW 0.2 0.1 0.2 0.1 0.3 0.4 0.7 0.4 0.7 1.6 CE-SDS %Purity 94.8 NT 94.6 94.2 NT 92.6 90.9 NT 91.8 86.7 NR %LMW 4.2 NT 4.4 4.5 NT 6.1 7.0 NT 6.2 10.7

[1072] %HMW 1.1 NT 1.1 1.3 NT 1.3 2.1 NT 2.1 2.7 CE-SDS %LC+HC 97.5 NT 97.2 97.2 NT 96.5 95.6 NT 95.4 94.2 R %LMW 1.4 NT 0.5 1.2 NT 0.8 2.0 NT 2.4 2.0

[1073] %HMW 1.2 NT 1.5 1.6 NT 1.9 2.4 NT 2.2 2.7 iCIEF %MP 61.6 60.7 62.4 65.1 58.0 57.0 51.4 53.0 47.9 34.8

[1074] %AP 29.2 31.4 27.2 24.0 33.5 30.9 36.4 36.8 41.9 51.2

[1075]

[1076] %BP 9.2 7.9 10.4 10.9 8.5 12.1 12.3 10.2 10.2 14.0 ELISA Construct 114 93 105 NT 88 97 NT 101 112 100 NT

[1077]

[1078] Potency%

[1079] SY = Slightly yellow; SO = Slightly opalescent liquid; EFP = essentially free of visible particles; AP = Acidic peak; MP = main peak; BP = basic peak; M = months; LC = light chain; HC = heavy chain; LMW = low molecular weight; BMW = high molecular weight; NT = not tested Example 3: Evaluation of formulations of Construct 114 stored in glass vials

[1080] A study was performed to evaluate the stability of formulations containing 150 mg / mL or 200 mg / mL of Construct 114, 10 mM L-histidine / L-histidine HC1, 120 mM L-arginine HC1, 10 mM L-methionine, 0.05 mM EDTA, and 0.05% (w / v) polysorbate 80, at pH 6.0. Formulations were stored in vials (glass vials sealed with elastomeric stoppers and aluminum crimp overseal, 2mL fill) and evaluated at various time points over the course of one month (for samples stored at 40 °C), six months (for samples stored at 25 °C), or 12 months (for samples stored at 5 °C) and after agitation (300 rpm and 25 °C for 3 days), 3 or 10 cycles of freeze / thaw (-80 °C to RT), or storage at high temperature (50 °C) to assess stability at various storage and stress conditions. The same assays performed in Examples 1 and 2 were used to assess the formulations. Data are provided in Tables 31-34.

[1081] There were no changes in visual appearance through 12 months of storage at 5 °C for any of the formulations tested. All formulations were slightly yellow, slightly opalescent, and free of visible particles.

[1082] Turbidity (A405) and protein concentration (A280) measurements were performed using UV- Visible spectrophotometry. All A405 and A280 measurements of turbidity and protein concentration for the tested formulations were within the expected ranges at all time points and storage conditions.

[1083] Osmolality and pH values remained consistent over time. The viscosities of all the samples were between 5 and 13 cP at 20 °C.

[1084] SEC was performed to quantify the higher molecular weight aggregated material and / or oligomers (HMW), monomer, and amounts of lower molecular weight material (LMW). SEC was performed using a Waters Acquity UPLC Protein BEH SEC column with a phosphate-buffered aqueous mobile phase. All formulations tested showed a high purity of approximately 98% as assessed by SEC at all time points through 12 months at 5 °C, with a less than 1% decrease in purity over the course of 12 months. The LMW species remained consistent with a range of about 0.1-0.2%. %. Faster HWM species formation was observed at a higher concentration of Construct 114, as expected.

[1085] icIEF analysis was performed on the samples to determine whether there were any changes in the main peaks, acidic species, and basic species over time at different storage conditions. No substantial changes were observed in charge variants over 12 months of storage at 5 °C as assessed by icIEF. Both formulations showed a change of 3-5% or less.

[1086] Potency was determined by performing a binding assay against the target, i.e., OX40L. The target antigen was immobilized onto a well plate and samples were added. The bound product reacted with a secondary antibody moiety generating a signal proportional to the amount of bound antibody. Relative binding potency of the sample was calculated using the EC50 of reference to samples on the same plate derived from 4-parameter logistic fit. The cell-based potency assay for Construct 114 utilized a Jurkat T cell-derived reporter line that expresses human 0X40 and a construct that produces luciferase when 0X40 ligand (OX40L) is bound to the 0X40 present on the cell surface. The potency of Construct 114 was maintained through 12 months of storage at 5 °C as assessed using ELISA for formulations at 150 mg / mL and as assessed by cell-based bioassay (CBA) and ELISA for formulations at 200 mg / mL across all storage conditions and timepoints.

[1087] Expected responses were observed in sub-visible particles and PS80 concentrations for all formulations through 12 months of storage at 5 °C. Product quality attributes for all formulations trended as expected when subjected to accelerated and stressed storage conditions as well as when subjected to multiple freeze-thaw cycling, mechanical agitation, and elevated thermal stresses. Table 31. Stability Data for 150 mg / mL Construct 114 Formulation

[1088] 150 mg / mL Construct 5 °C 25 °C 40 °C

[1089] 114 TO IM 3M 6M 12M IM 3M 6M 0.25M 0.5M IM SY, SY, SY, SY, SY, SY, SY, SY, SY, SY, SY, Appearance SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP SO, EFP Concentration (mg / mL) 150.5 149.4 149.5 152.1 152.4 148.8 150.9 155.1 147.8 149.5 149.0 Turbidity 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.11 0.11 0.11 0.11 Osmolality (mOsm / kg) 287 NT NT NT NT NT NT 289 NT NT 289 pH 5.9 NT NT NT NT NT NT 6.2 NT NT 6.1 PS80 (% w / v) 0.051 NT 0.050 0.046 0.054 NT 0.046 0.045 NT NT 0.051 SVP by > 2 pm 257 779 1734 1752 941 216 958 1351 154 802 481 MFI, > 10 pm 11 10 33 28 10 11 7 21 13 61 34 particles / mL

[1090] >25 pm 3 2 3 0 2 2 2 3 2 7 5 %Monomer

[1091] 98.8 98.8 98.0 98.3 98.3 98.5 98.4 97.4 97.9 97.3 96.3 SEC-UPLC %HMW 1.2 1.2 1.2 1.6 1.6 1.5 1.6 2.0 2.0 2.4 3.2

[1092] %LMW 0.0 0.0 0.0 0.1 0.1 0.0 0.2 0.6 0.2 0.2 0.5 %Purity 96.1 95.9 95.9 NT 95.1 95.5 94.6 NT 95.1 94.1 92.1 CE-SDS

[1093] NT 3.4 4.2 NT 6.2 NR %LMW 3.0 3.3 3.3 3.3 3.8 4.7

[1094] %HMW 0.9 0.9 0.9 NT 1.1 1.1 1.2 NT 1.1 1.2 1.7 %LC+HC 97.3 97.0 97.4 NT 97.4 97.2 97.4 NT 97.0 96.3 95.6 CE-SDS R %LMW 1.2 1.2 1.0 NT 1.2 1.3 1.2 NT 1.5 1.8 2.3

[1095] %HMW 1.6 1.8 1.6 NT 1.4 1.4 1.5 NT 1.4 1.9 2.1 %MP 59.7 58.4 60.4 60.8 65.7 56.2 54.2 47.6 57.1 48.8 44.4 iCIEF %AP 32.1 33.2 31.8 29.2 26.5 36.0 36.8 40.6 33.1 40.4 45.7

[1096]

[1097] %BP 8.1 8.4 7.8 10.0 7.8 7.8 9.0 11.8 9.8 10.8 9.9 ELISA Construct 114 92 94 NT NT 94 Potency% 97 88 97 106 97 99

[1098] CBA Construct 114

[1099] 97 88 92 94 89 106 97 99 NT NT 94 Potency%

[1100]

[1101] Viscosity (cP) at 20 °C 5.1 NT NT NT NT NT NT NT NT NT 5.3

[1102] Table 32. Stability Data for 150 mg / mL Construct 114 Formulation Under Stress Conditions

[1103] 150 mg / mL Construct Freeze / Thaw 50 °C

[1104] Agitation

[1105] 114 TO 3X 10X 0.25M

[1106] SY, SO, SY, SO, SY, SO, SY, SO, SY, SO,

[1107] Appearance

[1108] EFP EFP EFP EFP EFP

[1109] Concentration (mg / mL) 150.5 NT 150.8 149.1 148.5

[1110] Turbidity 0.1 NT 0.1 0.1 0.15

[1111] SVP by > 2 pm 257 NT 48243 105 142

[1112] MFI, > 10 pm 11 NT 1393 3 8

[1113] particles / mL

[1114] > 25 pm 3 NT 10 2 2

[1115] %Monomer 98.8 NT NT 98.8 86.7

[1116] SEC-UPLC %HMW 1.2 NT NT 1.2 12.9

[1117] %LMW 0 0 0 0 0.4

[1118] %MP 59.7 NT 60.6 61.1 55.5

[1119] iCIEF %AP 32.1 NT 31.7 31.1 36.7

[1120]

[1121] %BP 8.1 NT 7.8 7.8 7.8 Table 33. Stability Data for 200 mg / mL Construct 114 Formulation

[1122] 200 mg / mL Construct 5 °C 25 °C 40 °C

[1123] 114 TO IM 3M 6M 12M IM 3M 6M 0.25M 0.5M IM SY,

[1124] SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, SY, SO, Appearance EFP EFP EFP EFP SO, EFP EFP EFP EFP EFP EFP EFP

[1125] Concentration (mg / mL) 202.3 204 212.7 204.8 202.6 204.8 205 208.2 202.3 202.5 204.8 Turbidity 0.12 0.13 0.12 0.12 0.12 0.13 0.13 0.14 0.12 0.1 0.14 Osmolality (mOsm / kg) 307 NT NT NT NT NT NT 315 NT NT 309 PH 6.2 NT NT NT NT NT NT 6.2 NT NT 6.2 PS80 (% w / v) 0.056 0.053 0.054 0.041 0.054 0.052 0.047 0.041 NT NT 0.05 SVP by > 2 pm 141 853 941 1562 1840 480 12866 179970 429 144 465 MFI, ≥ 10 μm 67 26 51 52 47 13 213 2520 77 10 26 particles / mL

[1126] 00 > 25 pm 28 3 5 5 5 2 7 31 8 3 5 %Monomer 98.9 98.7 98.7 98.1 98.0 98.0 98.1 96.7 97.2 96.1 95.1 SEC-UPLC %HMW 1.1 1.3 1.3 1.8 1.9 2 1.7 2.6 2.7 3.6 4.4

[1127] %LMW 0 0 0 0.1 0.2 0.1 0.2 0.7 0.1 0.3 0.5 %Purity 94.6 94.9 95.4 95 91.6 94.6 94.1 91.4 92.7 91.4 91.5 CE-SDS %LMW 4.7 4.2 3.8 4.1 3.8 4.2 4.5 7.3 6.4 7 6.5 NR

[1128] %HMW 0.7 0.9 0.8 0.9 1.1 1.2 1.4 1.3 0.9 1.6 2 %LC+HC 97.6 96.1 97.2 96.9 97.4 97.3 96.5 95.2 96.3 97.7 95.7 CE-SDS R %LMW 1.3 2.5 1.4 1.2 1.2 1.4 1.6 2.1 1.9 1.3 2.5

[1129] %HMW 1.2 1.4 1.5 1.9 1.4 1.3 1.9 2.7 1.8 1 1.8 %MP 59.6 60.3 58.7 63.9 64.4 56.6 53.8 50.8 54.8 51.8 46.2 iCIEF %AP 29.6 31.6 33.3 27.7 27.0 34.4 37.1 39.0 35.3 37.4 43.1

[1130]

[1131] %BP 10.6 8.1 8.0 10.8 8.6 9.0 9.1 12.8 10.0 10.8 10.7 ELISA Construct 114

[1132] 94 98 79 129 112 88 103 118 NT NT 92 Potency%

[1133] CB A Construct 114

[1134] 98 95 91 107 100 103 91 91 NT NT 95 Potency%

[1135]

[1136] Viscosity (cP) at 20 °C 12.7 NT NT NT NT NT NT NT NT NT 12.6

[1137] Table 34. Stability Data for 200 mg / mL Construct 114 Formulation Under Stress Conditions

[1138] 200 mg / mL Construct Freeze / Thaw 50 °C

[1139] Agitation

[1140] 114 TO 3X 10X 0.25M

[1141] SY, SO, SY, SO, SY, SO, SY, SO, SY, SO,

[1142] Appearance

[1143] EFP EFP EFP EFP EFP

[1144] Concentration (mg / mL) 202.3 205.2 199.5 206.2 203.1

[1145] Turbidity 0.12 0.13 0.12 0.12 0.19

[1146] SVP by > 2 pm 141 4486 16509 265 337

[1147] MFI, > 10 pm 67 133 337 43 65

[1148] particles / mL > 25 pm 28 7 11 15 10

[1149] %Monomer 98.9 99 98.9 98.8 83.2

[1150] SEC-UPLC %HMW 1.1 1 1.1 1.2 16.4

[1151] %LMW 0 0 0 0 0.4

[1152] %MP 59.6 60 58.8 58.8 51.6

[1153] iCIEF %AP 29.6 31.8 33.2 33.1 35.4

[1154]

[1155] %BP 10.6 8.2 8 8.1 13 INCORPORATION BY REFERENCE

[1156] The entire disclosure of each of the patent and scientific documents referred to herein is incorporated by reference for all purposes.

[1157] EQUIVALENTS

[1158] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. INFORMAL SEQUENCE LISTING

[1159] Description Sequence SEQID NO

[1160] Kabat HCDR1 NYAMT SEQID NO: 1 Chothia HCDR1 GFTFSNY SEQID NO: 22 IMGT CDR1 GFTFSNY A SEQID NO: 44 Kabat HCDR2 LISGSGGLTKYADSVKG SEQID NO: 70 Chothia HCDR2 SGSGGL SEQID NO: 111 IMGT HCDR2 ISGSGGLT SEQID NO: 142 Kabat HCDR3 DEGLTTGEY SEQID NO: 175 Chothia HCDR3 EGLTTGE SEQID NO: 203 IMGTHCDR3 VKDEGLTTGEY SEQID NO: 223 Kabat LCDR1 RASQDIRNDLA SEQID NO: 258 Chothia LCDR1 SQDIRND SEQID NO: 286 IMGT LCDR1 QDIRND SEQID NO: 311 IMGT LCDR1 QSISSY SEQID NO: 334 Kabat LCDR2 ASSSLQS SEQID NO: 335 Chothia and ASS

[1161] IMGT LCDR2

[1162] Chothia and AAS

[1163] IMGTLCDR2

[1164] Kabat LCDR3 LQHNNYPFT SEQID NO: 368 Chothia and HNNYPF SEQID IMGT LCDR3 NO: 394 Heavy Chain EVQVVESGGGLVQPGGSLRLSCAASGFTFSNYAMTWVRQSP SEQID Variable Domain GKGLEWVSLISGSGGLTKYADSVKGRFTISRDNSKKTLFLQM NO: 419 1 NSLRAEDTAAYYCVKDEGLTTGEYWGQGTQVTVSS

[1165] Light Chain DIQMTQSPSSLSASVGDRVTITCRASQDIRNDLAWYQQKPGK SEQID Variable Domain APKRLIYASSSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATY NO: 489 1 YCLQHNNYPFTFGPGTKVDIK

[1166] Consensus X1X2AMX3, where X1= N, S, T, or I, X2= Y or H, and X3= T, Y,

[1167]

[1168] CDRH1 (Kabat) or S Consensus LIX1GX2GX3X4TX5YADSVX6G, where X1= S or T, X2= S or G, SEQID CDRH2 (Kabat) X3= G, A, or S, X4= L, S, I, or V, X5= K, H, N, or Y, and X6= K NO: 552 or R

[1169] Consensus X1EGLTX2GEX3, where X1= D or E, X2= T or S, and X3= Y, F, or SEQID CDRH3 (Kabat) S NO: 553 Consensus RX1SQX2IRNX3LX4, where X1= A or T, X2= D, G, or A, X3= D SEQID CDRL1 (Kabat) or N, and X4= A, G, or D NO: 554 Consensus X1X2SX3X4X5S, where X1= A or V, X2= S, V, T, or A, X3= S or N, CDRL2 (Kabat) X4= L or F, and X5= Q or K

[1170] Consensus LQHX1X2YPFX3, where X1= N or S, X2= N, S, or T, and X3= T or SEQID CDRL3 (Kabat) S NO: 556 Consensus GFTFX1X2X3, where X1= S, R, N, G, or T, X2= N, S, T, or I, and SEQID CDRH1 X3= Y or H NO: 557 (Chothia)

[1171] Consensus X1GX2GX3X4, where X1= S or T, X2= S or G, X3= G, A, or S, CDRH2 and X4= L, S, I, or V

[1172] (Chothia)

[1173] Consensus EGLTX1GE, where X1= T or S SEQID CDRH3 NO: 559 (Chothia)

[1174] Consensus SQX1IRNX2, where X1= D, G, or A, and X2= D or N SEQID CDRL1 NO: 560 (Chothia)

[1175] Consensus X1X2S, where Xi = A or V, and X2= S, V, T, or A

[1176] CDRL2

[1177] (Chothia)

[1178] Consensus HX1X2YPF, where X1= N or S, and X2= N, S, or T SEQID CDRL3 NO: 562 (Chothia)

[1179] Consensus GFTFX1X2X3A, where X1= S, R, N, G, or T, X2= N, S, T, or I, and SEQID CDRH1 (IMGT) X3= Y or H NO: 563 Consensus IX1GX2GX3X4T, where X1= S or T, X2= S or G, X3= G, A, or S, SEQID CDRH2 (IMGT) and X4= L, S, I, or V NO: 564 Consensus X1KX2EGLTX3GEX4, where X1= V or A, X2= D or E, X3= T or S, SEQID CDRH3 (IMGT) and X4= Y, F, or S NO: 565 Consensus QX1IRNX2, where X1= D, G, or A, and X2= D or N SEQID CDRL1 (IMGT) NO: 566 Consensus X1X2S, where Xi = A or V, and X2= S, V, T, or A

[1180] CDRL2 (IMGT)

[1181] Consensus LQHX1X2YPFX3, where X1= N or S, X2= N, S, or T, and X3= T or SEQID CDRL3 (IMGT) S NO: 568 Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 637 hlgGl* NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1182] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 638 hIgG4 DHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPK

[1183] DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK

[1184]

[1185] TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[1186] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 639 IgG4-SP DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[1187] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 640 IgG4-SPLE DHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[1188] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNV NO: 641 IgG2 DHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTFRVVSVLTWHQDWLNGKEYKCKVSNKGLP APIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1189] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 642 hIgGl-N297A NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1190] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 643 hIgGl-D265A NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1191] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 644 hlgGl-LALA NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1192] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 645

[1193]

[1194] hlgGl-LAGA NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1195] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 646 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFP LALAGA PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1196] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 647 hlgGl-LALAPG NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1197] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 648 hlgGl-YTE NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1198] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 649 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP N297A / YTE PKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1199] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 650 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP D265A / YTE PKPKDTLYITREPEVTCVVVAVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1200] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 651 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP LALA / YTE PKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL

[1201] VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL

[1202]

[1203] TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 652 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFP LAGA / YTE PKPKDTLYTTREPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1204] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 653 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFP LALAGA / YTE PKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1205] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 654 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP LALAPG / YTE PKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

[1206] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 655 hlgGl-LS NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[1207] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 656 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP N297A / LS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[1208] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 657 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP D265A / LS PKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[1209] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 658 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP LALA / LS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

[1210] NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN

[1211]

[1212] KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[1213] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 659 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFP LAGA / LS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[1214] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 660 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFP LALAGA / LS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[1215] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 661 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP LALAPG / LS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[1216] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 662 hlgGl-DHS NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[1217] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 663 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP N297A / DHS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYASTYRVVSVLTVDHHDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[1218] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 664 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP D265A / DHS PKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[1219] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 665 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP

[1220]

[1221] LALA / DHS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[1222] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 666 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFP LAGA / DHS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[1223] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 667 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFP LALAGA / DHS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[1224] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 668 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP LALAPG / DHS PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVDHHDWLNGKEYKCKVSN KALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[1225] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 669 hIgG4-YTE DHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPK DTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[1226] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 670 hIgG4-SP / YTE DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS

[1227] SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[1228] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 671 hIgG4- DHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPK SPLE / YTE DTLYITREPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPS SIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[1229] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID

[1230]

[1231] Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 672 hIgG4-LS DHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG

[1232] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 673 hIgG4-SP / LS DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG

[1233] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 674 hIgG4-SPLE / LS DHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG

[1234] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 675 hIgG4-DHS DHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHSHYTQKSLSLSLG

[1235] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 676 hIgG4-SP / DHS DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHSHYTQKSLSLSLG

[1236] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 677 hIgG4- DHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPK SPLE / DHS DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVDHHDWLNGKEYKCKVSNKGL PSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHSHYTQKSLSLSLG

[1237] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNV NO: 678 hIgG2-YTE DHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPK DTLYITREPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPA PIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS

[1238]

[1239] RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNV NO: 679 hIgG2-LS DHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTFRVVSVLTWHQDWLNGKEYKCKVSNKGLP APIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVLHEALHSHYTQKSLSLSPG

[1240] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNV NO: 680 hIgG2-DHS DHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTFRVVSVLTVDHHDWLNGKEYKCKVSNKGLP APIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHSHYTQKSLSLSPG

[1241] Heavy Chain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS SEQID Constant Region GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV NO: 681 IgG4-SP DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG

[1242] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 682 hlgGl-LA NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHAHYTQKSLSLSPG

[1243] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 683 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP N297A / LA PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHAHYTQKSLSLSPG

[1244] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 684 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFP D265A / LA PKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHAHYTQKSLSLSPG

[1245] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 685 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP LALA / LA PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH

[1246] NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN

[1247]

[1248] KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHAHYTQKSLSLSPG

[1249] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 686 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELAGAPSVFLFP LAGA / LA PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHAHYTQKSLSLSPG

[1250] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 687 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFP LALAGA / LA PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHAHYTQKSLSLSPG

[1251] Heavy Chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SEQID Constant Region SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NO: 688 hlgGl- NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFP LALAPG / LA PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCL VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVLHEALHAHYTQKSLSLSPG

[1252] Heavy Chain ASTKGPSVFPLAPSSKSTSG...

Claims

CLAIMS1. A formulation comprising:(a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL;(b) a histidine buffer, an acetate buffer, and / or a succinate buffer;(c) arginine and / or methionine or a salt solution thereof; and(d) a polysorbate or a poloxamer,wherein the formulation is at a pH of about 5.0 to about 7.0.

2. A formulation comprising:(a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL;(b) a histidine buffer, an acetate buffer, and / or a succinate buffer;(c) arginine and / or methionine or a salt solution thereof; and(d) a polysorbate or a poloxamer,wherein the formulation is at a pH of about 5.0 to about 7.0, andwherein the OX40L antibody comprises: a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:368.

3. A formulation comprising:(a) an OX40L antibody present at a concentration between about 125 mg / mL and about 250 mg / mL;(b) arginine and / or methionine or a salt solution thereof; and(c) a polysorbate or a poloxamer,wherein the formulation is at a pH of about 5.0 to about 7.0.

4. The formulation of any one of the above claims, wherein the formulation further comprises ethylenediaminetetraacetic acid (EDTA) or ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA).

5. The formulation of claim 4, comprising about 0.05 mM EDTA.

6. The formulation of any one of the above claims, wherein the formulation further comprises a sugar or sugar alcohol.

7. The formulation of any one of the above claims, wherein the OX40L antibody is present at a concentration between about 150 mg / mL and about 220 mg / mL.

8. The formulation of any one of the above claims, wherein the OX40L antibody is present at a concentration between about 160 mg / mL and about 220 mg / mL.

9. The formulation of claim 7, wherein the OX40L antibody is present at a concentration of about 150 mg / mL.

10. The formulation of claim 7 or 8, wherein the OX40L antibody is present at a concentration of about 200 mg / mL.

11. The formulation of any one of claims 1, 2, and 4- 10, wherein the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration between about 5 mM and about 20 mM.

12. The formulation of claim 11, wherein the histidine buffer, acetate buffer, and / or succinate buffer is at a concentration of about 10 mM.

13. The formulation of any one of claims 1, 2, and 4-12, wherein the histidine buffer comprises a histidine and a histidine salt.

14. The formulation of claim 13, wherein the histidine is L-histidine.

15. The formulation of claim 13 or 14, wherein the histidine salt is L-histidine HC1 monohydrate.

16. The formulation of any one of claims 1, 2, and 4-15, wherein the formulation comprises a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate.

17. The formulation of any one of the above claims, wherein the formulation comprises methionine, and wherein the methionine is L-methionine.

18. The formulation of claim 17, wherein the L-methionine is at a concentration between about 5 mM and about 15 mM.

19. The formulation of claim 18, wherein the L-methionine is at a concentration of about 10 mM.

20. The formulation of any one of the above claims, wherein the formulation comprises arginine, and wherein the arginine is L-arginine.

21. The formulation of claim 20, wherein the formulation comprises an L-arginine salt solution.

22. The formulation of claim 21, wherein the L-arginine salt solution salt solution comprises HC1 monohydrate.

23. The formulation of claim 21 or 22, wherein the L-arginine salt solution is at a concentration between about 40 mM and about 250 mM.

24. The formulation of claim 23, wherein the L-arginine salt solution is at a concentration of about 120 mM.

25. The formulation of any one of the above claims, wherein formulation comprises L-methionine at a concentration of about 10 mM and an L-arginine salt solution at a concentration of about 120 mM.

26. The formulation of any one of the above claims, wherein the formulation comprises a polysorbate, and wherein the polysorbate is at a concentration between about 0.01% w / v and about 0.15% w / v.

27. The formulation of any one of the above claims, wherein the polysorbate is at a concentration of about 0.05% w / v.

28. The formulation of any one of the above claims, wherein the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

29. The formulation of claim 28, wherein the polysorbate is polysorbate 80.

30. The formulation of any one of the above claims, wherein the formulation comprises polysorbate 80 at a concentration of about 0.05% w / v.

31. The formulation of any one of the above claims, wherein the formulation comprises a poloxamer, and wherein the poloxamer is poloxamer 188.

32. The formulation of any one of the above claims, wherein the formulation comprises a poloxamer, and wherein the poloxamer is at a concentration of about 0.1 mg / mL to about 0.5 mg / mL.

33. The formulation of any one of the above claims, wherein the pH is between about 5.5 and about 6.5.

34. The formulation of any one of the above claims, wherein the pH is between about 5.8 and about 6.2.

35. The formulation of claim 34, wherein the pH is about 6.0.

36. The formulation of any one of claims 1, 2, and 4-35, wherein the formulation comprises:(a) an OX40L antibody at a concentration of about 150 mg / mL to about 220 mg / mL; (b) a histidine buffer at a concentration of about 10 mM to about 15 mM, wherein the histidine buffer comprises L-histidine and L-histidine HCl monohydrate;(c) an L-arginine salt solution at a concentration of about 70 mM to about 130 mM; (d) L-methionine at a concentration of about 10 mM to about 15 mM; and(e) polysorbate 80 at a concentration of about 0.04% w / v to about 0.12% w / v, wherein the formulation is at a pH of about 5.8 to about 6.2.

37. The formulation of claim 36, wherein the OX40L antibody is at a concentration of about 150 mg / mL to about 200 mg / mL.

38. The formulation of claim 36 or 37, wherein the OX40L antibody is at a concentration of about 150 mg / mL.

39. The formulation of claim 36 or 37, wherein the OX40L antibody is at a concentration of about 200 mg / mL.

40. The formulation of any one of claims 36-39, wherein the formulation further comprises about 0.05 mM EDTA.

41. A formulation comprising:(a) an OX40L antibody present at a concentration of about 150 mg / mL;(b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate;(c) an L-arginine salt solution at a concentration of about 120 mM;(d) L-methionine at a concentration of about 10 mM; and(e) a polysorbate 80 at a concentration of about 0.05% w / v,wherein the formulation is at a pH of about 6.0.

42. A formulation comprising:(a) an OX40L antibody present at a concentration of about 200 mg / mL;(b) a histidine buffer at a concentration of about 10 mM, wherein the histidine buffer comprises L-histidine and L-histidine HC1 monohydrate;(c) an L-arginine salt solution at a concentration of about 120 mM;(d) L-methionine at a concentration of about 10 mM; and(e) a polysorbate 80 at a concentration of about 0.05% w / v,wherein the formulation is at a pH of about 6.0.

43. The formulation of claim 41 or 42, wherein the formulation further comprises ethylenediaminetetraacetic acid (EDTA) or EGTA.

44. The formulation of claim 43, comprising about 0.05 mM EDTA.

45. The formulation of any one of claims 41 to 44, wherein the formulation further comprises a sugar or sugar alcohol.

46. The formulation of claim 45, wherein the sugar or sugar alcohol is at a concentration between about 1% w / v and about 5% w / v.

47. The formulation of claim 46, wherein the sugar or sugar alcohol is at a concentration of about 3% w / v.

48. The formulation of any one of claims 45 to 47, wherein the sugar or sugar alcohol is a disaccharide.

49. The formulation of claim 48, wherein the disaccharide is sucrose.

50. The formulation of any one of the above claims, wherein the OX40L antibody comprises: a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:70, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:258, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:335, and a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 368.

51. The formulation of any one of the above claims, wherein the OX40L antibody comprises a heavy chain variable region sequence having at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to an amino acid sequence set forth in SEQ ID NO:419.

52. The formulation of any one of the above claims, wherein the OX40L antibody comprises a light chain variable region sequence having at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to an amino acid sequence set forth in SEQ ID NO: 489.

53. The formulation of any one of the above claims, wherein the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419.

54. The formulation of any one of the above claims, wherein the OX40L antibody comprises a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489.

55. The formulation of any one of the above claims, wherein the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419 and a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489.

56. The formulation of any one of the above claims, wherein the OX40L antibody is a humanized, human, or chimeric antibody.

57. The formulation of claim 56, wherein the OX40L antibody is a humanized antibody.

58. The formulation of any one of the above claims, wherein the OX40L antibody comprises a heavy chain human constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

59. The formulation of any one of the above claims, wherein the OX40L antibody comprises a human Fc region comprising a human heavy chain constant region of the class IgG and a subclass selected from IgGl, IgG2, IgG3, and IgG4.

60. The formulation of claim 59, wherein the human Fc region comprises a human IgGl Fc region.

61. The formulation of claim 59, wherein the human Fc region comprises a human IgG4 Fc region.

62. The formulation of claim 59, wherein the human Fc region comprises a human IgG2 Fc region.

63. The formulation of any one of the above claims, wherein the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 or SEQ ID NO: 924.

64. The formulation of claim 63, wherein the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651.

65. The formulation of claim 63, wherein the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 924.

66. The formulation of any one of the above claims, wherein the OX40L antibody comprises a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

67. The formulation of any one of the above claims, wherein the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 or SEQ ID NO: 924 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

68. The formulation of claim 67, wherein the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 651 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

69. The formulation of claim 67, wherein the OX40L antibody comprises a heavy chain comprising a constant heavy chain sequence set forth in SEQ ID NO: 924 and a light chain comprising a constant light chain sequence set forth in SEQ ID NO: 738.

70. The formulation of any one of the above claims, wherein the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 651 or SEQ ID NO: 924, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738.

71. The formulation of claim 70, wherein the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 651, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738.

72. The formulation of claim 70, wherein the OX40L antibody comprises a heavy chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:419, a constant heavy chain sequence set forth in SEQ ID NO: 924, a light chain variable region sequence comprising an amino acid sequence set forth in SEQ ID NO:489, and a constant light chain sequence set forth in SEQ ID NO: 738.

73. The formulation of any one of the above claims, wherein the OX40L antibody comprises an Fc region comprising one or more amino acid substitutions, wherein the one or more amino acid substitutions result in a change in antibody half-life, ADCC activity, ADCP activity, or CDC activity as compared to an otherwise equivalent antibody comprising an Fc region without the one or more amino acid substitutions.

74. The formulation of any one of the above claims, wherein the antibody comprises a human IgGl Fc region with LALA and / or YTE mutations.

75. The formulation of claim 74, the antibody comprises a human IgGl Fc region with LALA and YTE mutations.

76. The formulation of claim 74 or 75 wherein the LALA mutations are at positions 234 and 235 and the YTE mutations are at positions 252, 254 and 256.

77. The formulation of claim 74 or 75, wherein the LALA mutations are at positions 235 and 236 (L235A / L236A) by direct numbering and the YTE mutations at positions 253, 255, and 257 (M253Y / S255T / T257E) by direct numbering.

78. The formulation of any one of the above claims, wherein the OX40L antibody comprises an Fc region, and wherein the Fc region binds to Neonatal Fc receptor (FcRn).

79. The formulation of claim 78, wherein the Fc region of the antibody binds an FcRn with higher affinity at pH 6.0 compared to an antibody comprising a wild-type Fc region.

80. The formulation of claim 78 or 79, wherein the Fc region of the antibody binds to FcRn with a KD of <1 x 10-7M at pH 6.0.

81. The formulation of any one of the above claims, wherein the OX40L antibody is a monoclonal antibody.

82. The formulation of any one of the above claims, wherein the OX40L antibody binds an OX40L sequence set forth in SEQ ID NO: 739.

83. The formulation of any one of the above claims, wherein the formulation is suitable for subcutaneous administration.

84. The formulation of any one of the above claims, wherein the formulation is suitable for intravenous administration.

85. The formulation of any one of the above claims, wherein the formulation is sterile.

86. The formulation of any one of the above claims, wherein the OX40L antibody remains stable at 2 °C to 5 °C for at least six months, as determined by size exclusion chromatography (SEC).

87. The formulation of any one of the above claims, wherein the OX40L antibody remains stable at 2 °C to 5 °C for at least one year, as determined by SEC.

88. The formulation of any one of the above claims, wherein the OX40L antibody remains stable at 2 °C to 5 °C for at least two years, as determined by SEC.

89. The formulation of any one of the above claims, wherein the OX40L antibody remains stable at 2 °C to 5 °C for at least three years, as determined by SEC.

90. A vial, bag, or bottle comprising the formulation of any one of claims 1 to 89.

91. The vial of claim 90, wherein the vial is a prefilled syringe.

92. The vial of claim 90, wherein the vial is an autoinjector.

93. The vial of any one of claims 90-92, wherein an extractable volume of the vial is between 1.0 mL and 3.0 mL.

94. The vial of claim 93, wherein the extractable volume of the vial is about 2.0 mL.

95. The formulation or vial of any one of the above claims for use in the treatment of an inflammatory disorder or disease.

96. The formulation or vial of claim 95, for use in the treatment of atopic dermatitis.

97. The formulation or vial of claim 96, wherein the treatment reduces disease severity in a subject, and wherein disease severity is assessed by an atopic dermatitis disease severity outcome measure.

98. The formulation or vial of claim 95, for use in the treatment of an inflammatory disorder or disease selected from the group consisting of asthma, idiopathic pulmonary fibrosis, alopecia areata, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE), Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), of Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold Inducible Urticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA),Chronic Obstructive Pulmonary Disease (COPD), an inflammatory bowel disease, lupus, rheumatoid arthritis (RA), hidradenitis suppurativa, celiac disease, systemic sclerosis, allergic rhinitis, eosinophilic fasciitis, scleromyxedema, scleredema, and nephrogenic systemic fibrosis.

99. A therapeutic kit comprising: (i) a dose of the formulation of any one of claims 1 to 89 and (ii) a means for delivery of the formulation to a human.

100. The therapeutic kit of claim 99, wherein the means is a syringe.

101. The therapeutic kit of claim 99, wherein the means is an autoinjector.

102. The therapeutic kit of claim 99, wherein the means is an on-body injector.

103. The therapeutic kit of any one of claims 99-102 for use in treating an inflammatory disorder or disease in a human patient.

104. A kit comprising the vial of any one of claims 90-94 and instructions for use.

105. A method for treating an inflammatory disorder or disease in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation of any one of claims 1 to 89.

106. The method of claim 105, wherein the inflammatory disorder or disease is atopic dermatitis.

107. The method of claim 105, wherein the inflammatory disorder or disease is asthma, idiopathic pulmonary fibrosis, alopecia areata, chronic sinusitis with nasal polyps, Chronic Rhinosinusitis without Nasal Polyps (CRSsNP), eosinophilic esophagitis (EoE), an Eosinophilic gastrointestinal disorder or disease (EGID) selected from the group consisting of Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), Eosinophilic Colitis (EoC), and Eosinophilic Gastroenteritis (EGE), Churg-Strauss syndrome / Eosinophilic granulomatosis with polyangiitis (EGPA), Prurigo Nodularis (PN), of Chronic Spontaneous Urticaria (CSU), Chronic Pruritis of Unknown Origin (CPUO), Bullous Pemphigoid (BP), Cold InducibleUrticaria (ColdU), Allergic Fungal Rhinosinusitis (AFRS), Allergic Bronchopulmonary Aspergillosis (ABPA), Chronic Obstructive Pulmonary Disease (COPD), an inflammatory bowel disease, lupus, rheumatoid arthritis (RA), hidradenitis suppurativa, celiac disease, systemic sclerosis, allergic rhinitis, eosinophilic fasciitis, scleromyxedema, scleredema, or nephrogenic systemic fibrosis.

108. A method for treating a pathology associated with elevated levels of OX40L in a mammalian subject in need thereof, the method comprising administering to the mammalian subject a therapeutically effective amount of the formulation of any one of claims 1 to 89.

109. A method of manufacturing an intermediate preparation of an OX40L antibody comprising:(a) obtaining a purified preparation of the OX40L antibody; and(b) adjusting the matrix of the purified preparation of step (a), wherein adjusting the matrix comprises performing Ultrafiltration and Diafiltration (UFDF) with a diafiltration buffer comprising a histidine buffer and arginine or a salt solution thereof,wherein the diafiltration buffer is at a pH of from about 5.4 to about 7.0, thereby obtaining the intermediate preparation of the OX40L antibody.

110. The method of manufacturing of claim 109, wherein the intermediate preparation of the OX40L antibody has a higher concentration of the OX40L antibody relative to the purified preparation.

111. The method of manufacturing of claim 109 or 110, wherein the method of manufacturing further comprises:(c) formulating the intermediate preparation to obtain a formulation of the OX40L antibody.

112. The method of manufacturing of claim 111, wherein the formulation of the OX40L antibody comprises the formulation of any one of claims 1 to 89.

113. The method of manufacturing of claim 109, wherein the histidine buffer comprises a histidine and a histidine salt.

114. The method of manufacturing of claim 113, wherein the histidine is L-histidine.

115. The method of manufacturing of claim 113 or 114, wherein the histidine salt is L-histidine HC1 monohydrate.

116. The method of manufacturing of claim 109, wherein the arginine is L-arginine.

117. The method of manufacturing of claim 116, wherein the arginine is an L-arginine salt solution.

118. The method of manufacturing of claim 117, wherein the L-arginine salt solution salt solution comprises HC1 monohydrate.

119. The method of manufacturing of claim 118, wherein the L-arginine salt solution is at a concentration between 40 mM and 150 mM.

120. The method of manufacturing of claim 119, wherein the L-arginine salt solution is at a concentration of about 120 mM.

121. The method of manufacturing of claim 109, wherein the diafiltration buffer is at a pH of from 5.4 to 6.0.