Antibodies with FC modifications and methods of using the same

Abstract

The disclosure features anti-tumor necrosis factor receptor superfamily (TNFRSF), anti-tumor necrosis factor superfamily (TNFSF), anti-CD28, and anti-ICOS antibodies and antigen-binding fragments thereof with amino acid modifications at the Fc domain, and the use of these antibodies or antigen-binding fragments to modulate immune response. The antibodies and antigen-binding fragments thereof can be used to treat a wide variety of cancers, autoimmune disorders, neurological disorders, infectious diseases, inflammatory diseases, and transplant rejections.

Description

[0001] ANTIBODIES WITH FC MODIFICATIONS AND METHODS OF USING THE SAME

[0002] Sequence Listing

[0003] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on November 26, 2024, is named “00786-592WO5_Sequence_Listing_11_26_24” and is 1 ,383,907 bytes in size.

[0004] Background

[0005] Maintaining control of the cell-mediated and humoral immune responses is an important facet of healthy immune system activity. The aberrant regulation of lymphocyte-driven immune responses (e.g., T cell- and B cell-driven immune reactions) has been associated with a wide array of human diseases, as the inappropriate mounting of an immune response against various self and foreign antigens plays a causal role in such pathologies as autoimmune diseases, infectious diseases, inflammatory diseases, neurological diseases or disorders, allergies, graft-versus-host disease, transplantation graft rejections, and a variety of other immunological disorders. On the other hand, the use of immunotherapy is a prominent paradigm for ameliorating various human pathologies where insufficient or excessive immune responses are involved. Targeting signaling pathways within immune cells is a promising direction for the development of therapeutics for immunotherapy.

[0006] Proteins belonging to the tumor necrosis factor receptor superfamily (TNFRSF) and their ligands (TNFSF) are intimately involved in the activation, differentiation, and survival of cells of the immune system. TNFRSF members include, but may not be limited to, 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TNFR1 , TNFR2, TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3. TNFSF members include, but may not be limited to, TNF-a, TNF-p, lymphotoxin- p (LT-p), CD40L, FasL, CD30L, 4-1 BBL, CD27L, OX40L, TRAIL, LIGHT, RANKL, TWEAK, APRIL, BAFF, VEGI, EDA-A1 , EDA-A2, and GITRL. TNFRSF member proteins are oligomeric, type I or type III transmembrane proteins that contain multiple extracellular cysteine-rich domains. Several of these receptors contain intracellular death domains (DDs) that recruit caspase-interacting proteins following ligand binding to initiate the extrinsic pathway of caspase activation. Other TNF superfamily receptors that lack death domains bind TNF receptor-associated factors (TRAFs) and activate intracellular signaling pathways, such as the NF-KB pathway, that can lead to proliferation or differentiation of various cell types. In addition to these functions, several TNF superfamily receptors are also involved in regulating immune cell functions such as B-cell homeostasis and activation, natural killer cell activation, and T-cell co-stimulation. The signaling of TNFRSF member proteins, such as 4-1 BB and 0X40, and other costimulatory proteins such as CD28 and ICOS, are important in the regulation of immunity during inflammation and cancer.

[0007] Various antibodies or antigen-binding fragments that specifically bind TNFRSF member proteins and TNFSF member proteins, as well as CD28 and ICOS, with agonistic or antagonistic activities, have been described in the art. It is beneficial for a therapeutic antibody or antigen-binding fragment (e.g., an antibody or antigen-binding fragment that binds a TNFRSF member protein, a TNFSF member protein, CD28, or ICOS) to have a wide range of tolerable doses and dosing frequencies, so as to allow different dosing regimens for the treatment of specific diseases or disorders in different patient populations. It is also important to ensure that the antibody or antigenbinding fragment (e.g., an antibody or antigen-binding fragment that binds a TNFRSF member protein, a TNFSF member protein, CD28, or ICOS) can be administered at a high dose or dosing frequency without losing efficacy, as some studies have indicated that certain antibodies, when administered at high doses, lose efficacy due to nonproductive binding conformations (see, e.g., Mayes et al. Nat. Rev. Drug Discov. 17:509-527, 2018; incorporated herein by reference). Therefore, there remains a significant need for anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof that can be administered to and tolerated by a subject (e.g., a human subject) at a higher dose or dosing frequency and across a wide dose range that exhibit improved therapeutic profiles.

[0008] Summary of the Disclosure

[0009] The disclosure features methods of modulating an immune response in a subject by administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human TNFRSF member protein, a human TNFSF member protein, human CD28, or human ICOS. The disclosure also features anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments that contain one or more mutations within the Fc domain and constructs that contain the antibodies or antigen-binding fragments thereof. Additionally, the disclosure features polynucleotides, vectors, and host cells that may be used to produce the antibodies or antigen-binding fragments thereof or the constructs, pharmaceutical compositions and kits containing the antibodies or antigen-binding fragments thereof, constructs, polynucleotides, vectors, or host cells, and methods of modulating an immune response in a subject using the same.

[0010] In a first aspect, the disclosure features methods of modulating an immune response in a human subject comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human TNFRSF member protein, in which the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and further in which the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof of the disclosure can be administered to the human subject at a wide dose range. The dose range at which a modified antibody or antigen-binding fragment thereof of the disclosure can be administered may be broader than, e.g., a typical (or art-recognized) dose range of a corresponding unmodified antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof of the disclosure can be administered to the human subject at a dose range of about 10 mg to about 5000 mg, or a dose range of about 1 mg / kg to about 50 mg / kg.

[0011] In a second aspect, the disclosure features methods of modulating an immune response in a human subject comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human TNFRSF member protein, in which the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and further in which the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose and / or frequency that produces a greater modulation of the immune response relative to an unmodified antibody or antigen-binding fragment thereof administered at said dose and / or frequency. In some embodiments, the modified antibody or antigenbinding fragment thereof can be administered to the human subject at a wide dose range (e.g., a dose range that may be broader than, e.g., a typical (or art-recognized) dose range of a corresponding unmodified antibody or antigen-binding fragment thereof). The modified antibody or antigen-binding fragment thereof of the disclosure may be administered to the human subject at a frequency of one or more times a month, every three weeks, every two weeks, a week, every six days, every five days, every four days, every three days, every two days, or a day. The modified antibody or antigenbinding fragment thereof of the disclosure may also be administered to the human subject at a dose of about 10 mg to about 5000 mg, or at a dose of about 1 mg / kg to about 50 mg / kg. The modified antibody or antigen-binding fragment thereof of the disclosure can produce a greater (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) modulation (e.g., increase or enhancement; or decrease or suppression) of an immune response (e.g., an immune response against a cancer, such as cellular cytotoxicity and cytokine production; an immune response against an infection, such as antibody production, cytokine production, and cellular cytotoxicity; an immune response related to inflammation, such as cytokine production and activation of eosinophiles; or an immune response related to autoimmunity; among others) relative to an unmodified antibody or antigen-binding fragment thereof. An effect of a modified antibody or antigen-binding fragment thereof of the disclosure on the modulation of an immune response can be observed when the modified antibody or antigen-binding fragment thereof is administered to the human subject at a high dose and / or high dosing frequency, which is a dose or dosing frequency that is higher than a typical (or art-recognized) dose or dosing frequency of a corresponding unmodified antibody or antigen-binding fragment thereof. Methods for assessing modulation of an immune response are known in the art. See, e.g., Clay et al. Clin. Cancer Res. 7:1127-1135, 2001 ; Van der Burg et al. Sci. Transl. Med. 3:108ps44, 2011 ; Albert-Vega et al. Front. Immunol. 9:2367, 2018; incorporated herein by reference. In some embodiments, the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof. A higher dose and / or frequency is defined as a dose or dosing frequency that is higher than a typical (or art-recognized) dose or dosing frequency of the unmodified antibody or antigen-binding fragment thereof.

[0012] In some embodiments, the TNFRSF member protein is selected from the group consisting of TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3.

[0013] In some embodiments, the method further comprises determining (e.g., measuring) a pretreatment level of the soluble TNFRSF member protein in the serum or plasma of the human subject prior to the administration of one or more doses of the modified antibody or antigen-binding fragment thereof. In some embodiments, the method further comprises determining (e.g., measuring) a posttreatment level of the soluble TNFRSF member protein in the serum or plasma of the human subject after the administration of one or more doses of the modified antibody or antigen-binding fragment thereof. In some embodiments, the method further comprises determining (e.g., measuring) a reference level of the soluble TNFRSF member protein in the serum or plasma of a healthy human. In some cases, a reference level is determined in a subject prior to or after the administration of an antibody or antigen-binding fragment thereof disclosed herein, a construct disclosed herein, a polynucleotide disclosed herein, a vector disclosed herein, a host cell disclosed herein, or a pharmaceutical composition disclosed herein. For example, some non-limiting examples of reference levels of the soluble TNFRSF member protein include the level of the soluble TNFRSF member protein in a subject that has not been diagnosed as having a disease, does not present with at least two or more symptoms of a disease, or has not been administered with the anti-TNFRSF antibodies or antigen-binding fragments thereof disclosed herein. An exemplary reference level of soluble TNFR2 (sTNFR2) in the serum of a healthy human is about 2.51 ng / ml (see, e.g., Kartikasari et al. Front. Immunol. 16:13:918254, 2022; incorporated herein by reference).

[0014] In some embodiments, the modified antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein, and:

[0015] (a) the human subject has a pre-treatment level of the soluble TNFRSF member protein that is lower than or the same as the reference level of the soluble TNFRSF member protein; and / or

[0016] (b) the human subject has a post-treatment level of the soluble TNFRSF member protein that is higher than the reference level or the pre-treatment level of the soluble TNFRSF member protein, and in which the method further comprises administering one or more additional doses of the agonistic antibody or antigen-binding fragment thereof to the human subject in one or more additional treatment periods to maintain the higher level.

[0017] In some embodiments, the modified antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein, and:

[0018] (a) the human subject has a pre-treatment level of the soluble TNFRSF member protein that is higher relative to the reference level of the soluble TNFRSF member protein; and / or

[0019] (b) the human subject has a post-treatment level of the soluble TNFRSF member protein that is lower than the reference level or the pre-treatment level of the soluble TNFRSF member protein, and in which the method further comprises administering one or more additional doses of the antagonistic antibody or antigen-binding fragment thereof to the human subject in one or more additional treatment periods to maintain the lower level.

[0020] In some embodiments, the modified antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

[0021] In some embodiments, the TNFRSF member protein is TNFR2.

[0022] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) 1 (CDR-H1 ) comprising the amino acid sequence of X1X2X2X1X2X3X2JJJ, in which each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently Y, S, T, C, N, or Q; X3is D or E; and each J is independently a naturally occurring amino acid or is absent. In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTZ1Z2JJJ (SEQ ID NO: 1480), in which Z1is D or T; Z2is Y, F, or L; and each J is independently a naturally occurring amino acid or is absent. In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H2, a CDR-H3, a light chain CDR 1 (CDR-L1 ), a CDR-L2, and a CDR-L3 set forth in Table 2.

[0023] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-H1 comprising the amino acid sequence of X1X2X2X3X1, in which each X1is independently D or E; each X2is independently Y, S, T, C, N, or Q; and X3is L, A, V, G, I, M, W, F, or P. In some embodiments, the CDR-H1 comprises the amino acid sequence of DYNLD (SEQ ID NO: 1541 ). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0024] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-H2 comprising the amino acid sequence of X1X2X3X2X3X3X1X3X3X3X3X3X3X4X2X4X2, in which each X1is independently D or E; each X2is independently I, A, V, L, G, M, W, F, or P; each X3is independently N, S, T, C, Y, or Q; and each X4is independently K, R, or H. In some embodiments, the CDR-H2 comprises the amino acid sequence of DINPNYDSTSYSQKFRG (SEQ ID NO: 1542). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0025] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-H3 comprising the amino acid sequence of X1X2X2X1X2X1X3X1, in which each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently N, S, T, C, Y, or Q; and X3is D or E. In some embodiments, the CDR-H3 comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1543). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-L1 comprising the amino acid sequence of X1X2X1X1X1X2X3X4X1X1, in which each X1is independently S, Y, T, C, N, or Q; each X2is independently A, G, V, L, I, M, W, F, or P; X3is R, H, or K; and X4is Y, A, V, I, L, M, F, or W. In some embodiments, the CDR-L1 comprises the amino acid sequence of SASSSVRYNY (SEQ ID NO: 1544). In some embodiments, the antibody or antigenbinding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR- L2, and a CDR-L3 set forth in Table 2.

[0026] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-L2 comprising the amino acid sequence of X1X2X2X2X1X1X2, in which each X1is independently L, A, V, G, I, M, W, F, or P; and each X2is independently T, S, C, Y, N, or Q. In some embodiments, the CDR-L2 comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1545). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , and a CDR-L3 set forth in Table 2.

[0027] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-L3 comprising the amino acid sequence of X1X2X2X1X2X2X2X1X1X2, in which each X1is independently P, A, V, L, I, M, W, F, or G; and each X2is independently Q, S, T, C, N, or Y. In some embodiments, the CDR-L3 comprises the amino acid sequence of PQQWSSNPLT (SEQ ID NO: 1546). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , and a CDR-L2 set forth in Table 2.

[0028] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0029] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the sequences set forth in Table 3.

[0030] In some embodiments, the TNFRSF member protein is selected from the group consisting of CD27, CD40, GITR, 0X40, and 4-1 BB.

[0031] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of an antibody selected from the group consisting of varlilumab (CDX-1127), CDX-1140, SEA-CD40, R07009789, JNJ-64457107 (ADC1013), APX-005M, Chi Lob 7 / 4, TRX-518, MK-4166, MK-1248, GWN-323, INCAGN01876, BMS-986156, AMG-228, tavolimab (MEDI0562), PF-04518600, BMS-986178, MOXR-0916, GSK-3174998, INCAGN01949, utomilumab (PF-05082566), and urelumab (BMS- 663513).

[0032] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and the VL sequences of an antibody selected from the group consisting of varlilumab (CDX-1127), CDX-1140, SEA-CD40, R07009789, JNJ-64457107 (ADC1013), APX-005M, Chi Lob 7 / 4, TRX-518, MK-4166, MK-1248, GWN-323, INCAGN01876, BMS- 986156, AMG-228, tavolimab (MEDI0562), PF-04518600, BMS-986178, MOXR-0916, GSK-3174998, INCAGN01949, utomilumab (PF-05082566), and urelumab (BMS-663513).

[0033] In some embodiments, the human subject has a serum or plasma level of the soluble TNFRSF member protein that is lower than a reference level of the soluble TNFRSF member protein.

[0034] In some embodiments, the modified antibody or antigen-binding fragment thereof exerts one or more biological activities selected from the group consisting of:

[0035] (a) promoting NFKB activation;

[0036] (b) inducing the proliferation of a population of regulatory T (T-reg) cells;

[0037] (c) direct killing of, or promoting the death of, a population of CD8+ T cells;

[0038] (d) promoting an increase (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) in the level of one or more mRNA molecules encoding a protein selected from the group consisting of clAP2, TRAF2, Etk, VEGFR2, PI3K, Akt, a protein involved in the angiogenic pathway, an IKK complex, RIP, NIK, MAP3K, a protein involved in the NFKB pathway, NIK, JNK, AP-1 , a MEK, MKK3, NEMO, IL2R, Foxp3, IL2, TNF, lymphotoxin a, and lymphotoxin p;

[0039] (e) promoting an increase (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) in the level of one or more proteins selected from the group consisting of clAP2, TRAF2, Etk, VEGFR2, PI3K, Akt, a protein involved in the angiogenic pathway, an IKK complex, RIP, NIK, MAP3K, a protein involved in the NFKB pathway, NIK, JNK, AP-1 , a MEK, MKK3, NEMO, IL2R, Foxp3, IL2, TNF, lymphotoxin a, and lymphotoxin p;

[0040] (f) promoting an increase (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) in the level of itaconate; and

[0041] (g) promoting an increase (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) in the level of the soluble TNFRSF member protein. In some embodiments, the modified antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

[0042] In some embodiments, the TNFRSF member protein is TNFR2.

[0043] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 4.

[0044] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the sequences set forth in Table 5.

[0045] In some embodiments, the human subject has a serum or plasma level of the soluble TNFRSF member protein that is higher than a reference level of the soluble TNFRSF member protein.

[0046] In some embodiments, the modified antibody or antigen-binding fragment thereof exerts one or more biological activities selected from the group consisting of:

[0047] (a) inhibiting NFKB activation;

[0048] (b) reducing or inhibiting the proliferation of a population of T-reg cells;

[0049] (c) inducing the proliferation of a population of CD8+ T cells;

[0050] (d) reducing or inhibiting the proliferation of a population of cancer cells;

[0051] (e) inhibiting the TNFRSF member protein signaling in proliferating cells;

[0052] (f) not inhibiting the TNFRSF member protein signaling in resting cells;

[0053] (g) reducing or inhibiting the proliferation of a population of myeloid-derived suppressor cells (MDSCs);

[0054] (h) promoting a decrease (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) in the level of one or more mRNA molecules encoding a protein selected from the group consisting of clAP2, TRAF2, Etk, VEGFR2, PI3K, Akt, a protein involved in the angiogenic pathway, an IKK complex, RIP, NIK, MAP3K, a protein involved in the NFKB pathway, NIK, JNK, AP-1 , a MEK, MKK3, NEMO, IL2R, Foxp3, IL2, TNF, lymphotoxin a, and lymphotoxin p;

[0055] (i) promoting a decrease (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) in the level of one or more proteins selected from the group consisting of clAP2, TRAF2, Etk, VEGFR2, PI3K, Akt, a protein involved in the angiogenic pathway, an IKK complex, RIP, NIK, MAP3K, a protein involved in the NFKB pathway, NIK, JNK, AP-1 , a MEK, MKK3, NEMO, IL2R, Foxp3, IL2, TNF, lymphotoxin a, and lymphotoxin p; and

[0056] (j) promoting a decrease (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) in the level of the soluble TNFRSF member protein. In some embodiments, the modified antibody or antigen-binding fragment thereof is neither an agonist nor an antagonist of the TNFRSF member protein.

[0057] In some embodiments, the TNFRSF member protein is TNFR2.

[0058] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 6.

[0059] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the sequences set forth in Table 7.

[0060] In some embodiments, the modified antibody or antigen-binding fragment thereof has less than 90% (e.g., less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%) cross-reactivity with the soluble TNFRSF member protein. In some embodiments, the modified antibody or antigen-binding fragment thereof has less than 50% cross-reactivity with the soluble TNFRSF member protein. For example, the antibody or antigen-binding fragment thereof may bind TNFR2 but exhibits less than 50% cross-reactivity (e.g., less than 40%, 30%, 20%, or 10% cross-reactivity) to soluble TNFR2. The cross-reactivity of an antibody or antigen-binding fragment thereof with an antigen can be determined using methods that are known in the art, such as by assessing the percentage homology of an antigen sequence of a protein bound by an antibody with the sequence of a second protein. A high percentage of homology indicates that the antibody is likely to cross reacts with the second protein. Cross-reactivity of an antibody or antigen-binding fragment thereof with an antigen can be determined by using a biophysical technique, such as a Surface Plasmon Resonance (SPR)-based assay or a Biacore binding assay.

[0061] In a third aspect, the disclosure features methods of modulating an immune response in a human subject comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human TNFSF member protein, in which the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and further in which the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof can be administered to the human subject at a wide dose range (e.g., a dose range that may be broader than, e.g., a typical (or art-recognized) dose range of a corresponding unmodified antibody or antigen-binding fragment thereof).

[0062] In a fourth aspect, the disclosure features methods of modulating an immune response in a human subject comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human TNFSF member protein, in which the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and further in which the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose and / or frequency that produces a greater modulation of the immune response relative to an unmodified antibody or antigen-binding fragment thereof administered at said dose and / or frequency. In some embodiments, the modified antibody or antigenbinding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof can be administered to the human subject at a wide dose range (e.g., a dose range that may be broader than, e.g., a typical (or art-recognized) dose range of a corresponding unmodified antibody or antigen-binding fragment thereof).

[0063] In some embodiments, the TNFSF member protein is TRAIL.

[0064] In a fifth aspect, the disclosure features methods of modulating an immune response in a human subject comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds human CD28, in which the modified antibody or antigenbinding fragment thereof comprises an Fc domain with one or more amino acid modifications, and further in which the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigenbinding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof can be administered to the human subject at a wide dose range (e.g., a dose range that may be broader than, e.g., a typical (or art-recognized) dose range of a corresponding unmodified antibody or antigen-binding fragment thereof).

[0065] In a sixth aspect, the disclosure features methods of modulating an immune response in a human subject comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds human CD28, in which the modified antibody or antigenbinding fragment thereof comprises an Fc domain with one or more amino acid modifications, and further in which the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose and / or frequency that produces a greater modulation of the immune response relative to an unmodified antibody or antigen-binding fragment thereof administered at said dose and / or frequency. In some embodiments, the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof can be administered to the human subject at a wide dose range (e.g., a dose range that may be broader than, e.g., a typical (or art-recognized) dose range of a corresponding unmodified antibody or antigen-binding fragment thereof).

[0066] In some embodiments, the modified antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds CD28. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of theralizumab (TAB-08). In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of theralizumab (TAB-08).

[0067] In a seventh aspect, the disclosure features methods of modulating an immune response in a human subject comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds human ICOS, in which the modified antibody or antigenbinding fragment thereof comprises an Fc domain with one or more amino acid modifications, and further in which the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigenbinding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof can be administered to the human subject at a wide dose range (e.g., a dose range that may be broader than, e.g., a typical (or art-recognized) dose range of a corresponding unmodified antibody or antigen-binding fragment thereof).

[0068] In an eighth aspect, the disclosure features methods of modulating an immune response in a human subject comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds human ICOS, in which the modified antibody or antigenbinding fragment thereof comprises an Fc domain with one or more amino acid modifications, and further in which the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose and / or frequency that produces a greater modulation of the immune response relative to an unmodified antibody or antigen-binding fragment thereof administered at said dose and / or frequency. In some embodiments, the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof can be administered to the human subject at a wide dose range (e.g., a dose range that may be broader than, e.g., a typical (or art-recognized) dose range of a corresponding unmodified antibody or antigen-binding fragment thereof).

[0069] In some embodiments, the modified antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds ICOS. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of GSK-3359609 or JTX-2011 . In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of GSK-3359609 or JTX-2011 .

[0070] In some embodiments, one or more doses of the modified antibody or antigen-binding fragment thereof is administered to the human subject in one or more treatment periods, in which each dose comprises from about 0.1 mg to about 5000 mg of the modified antibody or antigen-binding fragment thereof. In some embodiments, each dose comprises from about 0.001 mg / kg to about 50 mg / kg of the modified antibody or antigen-binding fragment thereof. In some embodiments, each treatment period lasts one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, or more.

[0071] In some embodiments, the modified antibody or antigen-binding fragment thereof is administered to the human subject at a frequency of one or more times a month, every three weeks, every two weeks, a week, every six days, every five days, every four days, every three days, every two days, or a day.

[0072] In some embodiments, the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose of about 10 mg to about 5000 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered to the human subject at a dose of about 1 mg / kg to about 50 mg / kg.

[0073] In some embodiments, the one or more amino acid modifications comprise one or more substitutions, deletions, insertions, or chemical modifications of the Fc domain.

[0074] In some embodiments, the modified antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, and a chimeric antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof is a human, humanized, or chimeric antibody or antigen-binding fragment thereof.

[0075] In some embodiments, the one or more amino acid modifications at the Fc domain decrease (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) the binding affinity of the modified antibody or antigen-binding fragment thereof for an Fc receptor relative to the corresponding unmodified antibody or antigen-binding fragment thereof. A decrease (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) in the binding affinity of the antibody or antigen-binding fragment thereof of the disclosure for an Fc receptor may manifest as an equilibrium dissociation constant (KD) between the antibody or antigen-binding fragment thereof and its antigen (e.g., a TNFRSF member protein) that is higher (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) than the KD between an unmodified antibody or antigen-binding fragment thereof and the antigen. The KD between an antibody or antigen-binding fragment thereof and an antigen can be measured by methods such as surface plasmon resonance (SPR) (e.g., using BIACORE™ systems). In some embodiments, the effector function of the modified antibody or antigen-binding fragment thereof is not dependent on antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP). The effector function (e.g., ADCC or ADCP) of the antibody or antigen-binding fragment thereof of the disclosure may be determined by methods that are known in the art (see, e.g., Parekh et al. MAbs 4:310-318, 2012; and Kamen et al. J. Immunol. Methods 468:55-60, 2019). In some embodiments, the one or more amino acid modifications at the Fc domain improve a biological activity of the modified antibody or antigenbinding fragment thereof relative to the corresponding unmodified antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof exhibits dimeric binding with its antigen (e.g., a TNFRSF member protein, a TNFSF member protein, CD28, or ICOS) at a high dose, in which the modified antibody or antigen-binding fragment thereof comprises a first arm and a second arm, further in which the first arm binds to the antigen, and the second arm binds to an adjacent protein (e.g., an adjacent antigen of the antibody or antigen-binding fragment thereof). In some embodiments, the modified antibody or antigen-binding fragment thereof forms a hexagonal network with its antigen (e.g., a TNFRSF member protein, a TNFSF member protein, CD28, or ICOS) at a high dose.

[0076] In some embodiments, the Fc receptor is selected from the group consisting of FcyRI, FcyRII, and FcyRI 11. In some embodiments, the biological activity of the modified antibody or antigen-binding fragment thereof is independent of ADCC or ADCP. In some embodiments, the adjacent protein is an antigen of the antibody or antigen-binding fragment thereof (e.g., a TNFRSF member protein, a TNFSF member protein, CD28, or ICOS).

[0077] In some embodiments, the Fc domain is selected from the group consisting of an IgG Fc domain, an IgA Fc domain, an IgD Fc domain, an IgE Fc domain, and an IgM Fc domain.

[0078] In some embodiments, the Fc domain is an IgG Fc domain.

[0079] In some embodiments, the Fc domain is a human IgG 1 Fc domain. In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0080] (i) L235E;

[0081] (ii) L234A and L235A;

[0082] (iii) L234A, L235A, and P329G

[0083] (iv) L234E, L235F, and P331 S;

[0084] (v) D265A;

[0085] (vi) G237A;

[0086] (vii) E318A;

[0087] (viii) E233P

[0088] (ix) G236R and L328R;

[0089] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0090] (xi) N297G or N297Q, in which the amino acid positions are numbered according to the EU index. In some embodiments, the modified antibody or antigen-binding fragment thereof is an IgG 1 antibody or antigen-binding fragment thereof.

[0091] In some embodiments, the Fc domain is a human lgG2 Fc domain. In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0092] (i) D265A;

[0093] (ii) G237A;

[0094] (iii) E318A;

[0095] (iv) H268Q, V309L, A330S, and P331 S;

[0096] (v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and

[0097] (vi) N297G or N297Q, in which the amino acid positions are numbered according to the EU index.

[0098] In some embodiments, the modified antibody or antigen-binding fragment thereof is an lgG2 antibody or antigen-binding fragment thereof.

[0099] In some embodiments, the modified antibody or antigen-binding fragment thereof is an lgG3 antibody or antigen-binding fragment thereof.

[0100] In some embodiments, the Fc domain is a human lgG3 Fc domain. In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0101] (i) L235E;

[0102] (ii) L234A and L235A;

[0103] (iii) L234A, L235A, and P329G

[0104] (iv) L234E, L235F, and P331 S;

[0105] (v) D265A;

[0106] (vi) G237A;

[0107] (vii) E318A;

[0108] (viii) E233P

[0109] (ix) G236R and L328R;

[0110] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0111] (xi) N297G or N297Q, in which the amino acid positions are numbered according to the EU index.

[0112] In some embodiments, the Fc domain is a human lgG4 Fc domain. In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0113] (i) L235E;

[0114] (ii) D265A;

[0115] (iii) G237A; (iv) E318A;

[0116] (v) E233P

[0117] (vi) G236R and L328R; and

[0118] (vii) N297G or N297Q, in which the amino acid positions are numbered according to the EU index.

[0119] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P (S241 P according to Kabat). In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0120] (i) L235E; and

[0121] (ii) F234A and L235A, in which the amino acid positions are numbered according to the EU index.

[0122] In some embodiments, the modified antibody or antigen-binding fragment thereof is an lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the amino acid substitution S228P.

[0123] In some embodiments, the modified antibody or antigen-binding fragment thereof does not comprise any one of the amino acid substitutions set forth in Table 18, in which the amino acid positions are numbered according to the EU index.

[0124] In some embodiments, the one or more amino acid modifications are one or more amino acid deletions. In some embodiments, the one or more amino acid deletions are deletions of all amino acid residues of the Fc domain. In some embodiments, the modified antibody or antigen-binding fragment thereof lacks an Fc domain. In some embodiments, the modified antibody or antigenbinding fragment thereof is selected from the group consisting of a single-chain Fv molecule (scFv), a diabody, a triabody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab’)2 molecule, and a tandem scFv (taFv).

[0125] In some embodiments, the modified antibody or antigen-binding fragment thereof is conjugated to a therapeutic agent. In some embodiments, the therapeutic agent is selected from the group consisting of a chemotherapy agent, an immunotherapy agent, an agonist of a TNFRSF member protein, an antagonist of a TNFRSF member protein, an agonist of a TNFSF member protein, an antagonist of a TNFSF member protein, an agonist of CD28, an antagonist of CD28, an agonist of ICOS, and an antagonist of ICOS.

[0126] In some embodiments, the method comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of a chemotherapy agent, an immunotherapy agent, an agonist of a TNFRSF member protein, an antagonist of a TNFRSF member protein, an agonist of a TNFSF member protein, an antagonist of a TNFSF member protein, an agonist of CD28, an antagonist of CD28, an agonist of ICOS, and an antagonist of ICOS. In some embodiments, the modified antibody or antigen-binding fragment thereof is administered to the human subject intravenously or subcutaneously. In some embodiments, the modified antibody or antigen-binding fragment thereof is administered to the human subject subcutaneously.

[0127] In some embodiments, the method inhibits an immune response mediated by a B cell, a CD8+ T cell, or a T-reg cell in the human subject.

[0128] In some embodiments, the method promotes an immune response mediated by a B cell, a CD8+ T cell, or a T-reg cell in the human subject.

[0129] In some embodiments, the human subject is in need of a tissue or organ regeneration. In some embodiments, the tissue or organ is selected from the group consisting of a pancreas, islets, salivary gland, pituitary gland, kidney, heart, lung, hematopoietic system, cranial nerves, heart, aorta, olfactory gland, ear, nerves, structures of the head, eye, thymus, tongue, bone, liver, small intestine, large intestine, gut, lung, brain, skin, peripheral nervous system, central nervous system, spinal cord, breast, embryonic structures, embryos, and testes.

[0130] In some embodiments, the method is for treating a cell proliferation disorder in the human subject. In some embodiments, the cell proliferation disorder is a cancer selected from the group consisting of leukemia, lymphoma, liver cancer, bone cancer, lung cancer, brain cancer, bladder cancer, gastrointestinal cancer, breast cancer, cardiac cancer, cervical cancer, uterine cancer, head and neck cancer, gallbladder cancer, laryngeal cancer, lip and oral cavity cancer, ocular cancer, melanoma, pancreatic cancer, prostate cancer, colorectal cancer, testicular cancer, and throat cancer. In some embodiments, the cell proliferation disorder is cancer selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), adrenocortical carcinoma, AIDS-related lymphoma, primary central nervous system (CNS) lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, extrahepatic cancer, Ewing sarcoma family, osteosarcoma and malignant fibrous histiocytoma, central nervous system embryonal tumors, central nervous system germ cell tumors, craniopharyngioma, ependymoma, bronchial tumors, Burkitt lymphoma, carcinoid tumor, primary lymphoma, chordoma, chronic myeloproliferative neoplasms, colon cancer, extrahepatic bile duct cancer, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, fibrous histiocytoma of bone, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), testicular germ cell tumor, gestational trophoblastic disease, glioma, childhood brain stem glioma, hairy cell leukemia, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, islet cell tumors, pancreatic neuroendocrine tumors, Wilms tumor and other childhood kidney tumors, Langerhans cell histiocytosis, small cell lung cancer, cutaneous T-cell lymphoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract carcinoma, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm (e.g., multiple myeloma or refractory multiple myeloma), myelodysplastic syndromes, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma (NHL), nonsmall cell lung cancer (NSCLC), epithelial ovarian cancer, germ cell ovarian cancer, low malignant potential ovarian cancer, pancreatic neuroendocrine tumors, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary peritoneal cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, rhabdomyosarcoma, Sezary syndrome, small intestine cancer, soft tissue sarcoma, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, urethral cancer, endometrial uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Waldenstrom macroglobulinemia. In some embodiments, the modified antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein selected from the group consisting of TRAIL-R1 (TNFRSF1 OA), TRAIL-R2 (TNFRSF1 OB), TNFR1 , Fas, CD40, CD27, 4-1 BB, 0X40, GITR, and XEDAR. In some embodiments, the modified antibody or antigen-binding fragment thereof is an antagonistic antibody or antigenbinding fragment thereof that specifically binds a TNFRSF member protein selected from the group consisting of TRAMP, NGFR, TRAIL-R4, TNFR2, HVEM, CD30, TROY, and RELT. In some embodiments, the modified antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprising a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 4. In some embodiments, the modified antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprising a VH and a VL having amino acid sequences that are at least 80% identical to the sequences set forth in Table 5.

[0131] In some embodiments, the method is for treating an autoimmune disease or an inflammatory disease in the human subject. In some embodiments, the autoimmune disease is selected from the group consisting of Type I diabetes, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behget’s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg- Strauss syndrome, cicatricial pemphigoid, limited scleroderma (CREST syndrome), cold agglutinin disease, Crohn’s disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome (ALPS), idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP) , IgA nephropathy, juvenile arthritis, lichen planus, lupus, lupus nephritis, Meniere’s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pemphigus foliaceus, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter’s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, Stiff- Man syndrome, Takayasu’s arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, Wegener’s granulomatosis, Goodpasture syndrome, transplant rejection, celiac disease, esophagitis, and inflammatory central nervous system disorders. In some embodiments, the inflammatory central nervous system disorder is Alzheimer’s disease.

[0132] In some embodiments, the method is for treating an infectious disease in the human subject. In some embodiments, the infectious disease is caused by one or more agents selected from the group consisting of a virus, a bacterium, a fungus, and a parasite. In some embodiments, the infectious disease is caused by a virus selected from the group consisting of hepatitis C virus, Yellow fever virus, Kadam virus, Kyasanur Forest disease virus, Langat virus, Omsk hemorrhagic fever virus, Powassan virus, Royal Farm virus, Karshi virus, tick-borne encephalitis virus, Neudoerfl virus, Sofjin virus, Louping ill virus, Negishi virus, Meaban virus, Saumarez Reef virus, Tyuleniy virus, Aroa virus, dengue virus, Kedougou virus, Cacipacore virus, Koutango virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Usutu virus, West Nile virus, Yaounde virus, Kokobera virus, Bagaza virus, llheus virus, Israel turkey meningoencephalo-myelitis virus, Ntaya virus, Tembusu virus, Zika virus, Banzi virus, Bouboui virus, Edge Hill virus, Jugra virus, Saboya virus, Sepik virus, Uganda S virus, Wesselsbron virus, yellow fever virus, Entebbe bat virus, Yokose virus, Apoi virus, Cowbone Ridge virus, Jutiapa virus, Modoc virus, Sal Vieja virus, San Perlita virus, Bukalasa bat virus, Carey Island virus, Dakar bat virus, Montana myotis leukoencephalitis virus, Phnom Penh bat virus, Rio Bravo virus, Tamana bat virus, cell fusing agent virus, Ippy virus, Lassa virus, lymphocytic choriomeningitis virus (LCMV), Mobala virus, Mopeia virus, Amapari virus, Flexal virus, Guanarito virus, Junin virus, Latino virus, Machupo virus, Oliveros virus, Parana virus, Pichinde virus, Pirital virus, Sabia virus, Tacaribe virus, Tamiami virus, Whitewater Arroyo virus, Chapare virus, Lujo virus, Hantaan virus, Sin Nombre virus, Dugbe virus, Bunyamwera virus, Rift Valley fever virus, La Crosse virus, California encephalitis virus, Crimean-Congo hemorrhagic fever (CCHF) virus, Ebola virus, Marburg virus, Venezuelan equine encephalitis virus (VEE), Eastern equine encephalitis virus (EEE), Western equine encephalitis virus (WEE), Sindbis virus, rubella virus, Semliki Forest virus, Ross River virus, Barmah Forest virus, O’nyong’nyong virus, chikungunya virus, smallpox virus, monkeypox virus, vaccinia virus, herpes simplex virus, human herpes virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella-Zoster virus, Kaposi’s sarcoma associated-herpesvirus (KSHV), influenza virus, severe acute respiratory syndrome (SARS) virus, rabies virus, vesicular stomatitis virus (VSV), human respiratory syncytial virus (RSV), Newcastle disease virus, hendravirus, nipahvirus, measles virus, rinderpest virus, canine distemper virus, Sendai virus, human parainfluenza virus (e.g., 1 , 2, 3, and 4), rhinovirus, mumps virus, poliovirus, human enterovirus (e.g., A, B, C, and D), hepatitis A virus, coxsackievirus, hepatitis B virus, human papilloma virus, adeno- associated virus, astrovirus, JC virus, BK virus, SV40 virus, Norwalk virus, rotavirus, human immunodeficiency virus (HIV), and human T-lymphotropic virus Types I and II. In some embodiments, the infectious disease is caused by a bacterium belonging to a genus selected from the group consisting of Salmonella, Streptococcus, Bacillus, Listeria, Corynebacterium, Nocardia, Neisseria, Actinobacter, Moraxella, Enterobacteriacece, Pseudomonas, Escherichia, Klebsiella, Serratia, Enterobacter, Proteus, Salmonella, Shigella, Yersinia, Haemophilus, Bordatella, Legionella, Pasturella, Francisella, Brucella, Bartonella, Clostridium, Vibrio, Campylobacter, and Staphylococcus. In some embodiments, the infectious disease is caused by a fungus belonging to a genus selected from the group consisting of Aspergillus, Candida, Malassezia, Trichosporon, Fusarium, Acremonium, Rhizopus, Mucor, Pneumocystis, and Absidia. In some embodiments, the infectious disease is caused by a parasite selected from the group consisting of Entamoeba hystolytica, Giardia lamblia, Cryptosporidium muris, Trypanosomatida gambiense, Trypanosomatida rhodesiense, Trypanosomatida crusi, Leishmania mexicana, Leishmania braziliensis, Leishmania tropica, Leishmania donovani, Toxoplasma gondii, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium falciparum, Trichomonas vaginalis, and Histomonas meleagridis. Exemplary helminthic parasites include richuris trichiura, Ascaris lumbricoides, Enterobius vermicularis, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Wuchereria bancrofti, and Dracunculus medinensis, Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, Fasciola hepatica, Fasciola gigantica, Heterophyes, Paragonimus westermani, Taenia solium, Taenia saginata, Hymenolepis nana, and Echinococcus granulosus.

[0133] In some embodiments, the method is for treating an inflammatory disease in the human subject. In some embodiments, the inflammatory disease is selected from the group consisting of acute or chronic inflammation, cardiac fibrosis, lung fibrosis, osteoarthritis, rheumatoid arthritis, atherosclerosis, type I diabetes, type II diabetes, graft-versus-host disease, multiple sclerosis, osteomyelitis, psoriasis, Crohn’s disease, Sjogren’s syndrome, lupus erythematosus, and ulcerative colitis.

[0134] In some embodiments, the method is for treating a neurological disease or disorder in the human subject. In some embodiments, the neurological disease or disorder is selected from the group consisting of a brain tumor, a brain metastasis, a brain injury, a spinal cord injury, a nerve injury, schizophrenia, epilepsy, Parkinson’s disease, autism, Huntington’s disease, stroke, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and myasthenia gravis. In some embodiments, the method is for treating an allergy in the human subject. In some embodiments, the allergy is selected from the group consisting of food allergy, seasonal allergy, pet allergy, hives, hay fever, allergic conjunctivitis, poison ivy allergy oak allergy, mold allergy, drug allergy, dust allergy, cosmetic allergy, and chemical allergy.

[0135] In some embodiments, the method is for treating a transplant rejection in the human subject. In some embodiments, the transplant rejection is an allograft rejection. In some embodiments, the transplant rejection is selected from the group consisting of skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection. In some embodiments, the ligament graft rejection is selected from the group consisting of cricothyroid ligament graft rejection, periodontal ligament graft rejection, suspensory ligament of the lens graft rejection, palmar radiocarpal ligament graft rejection, dorsal radiocarpal ligament graft rejection, ulnar collateral ligament graft rejection, radial collateral ligament graft rejection, suspensory ligament of the breast graft rejection, anterior sacroiliac ligament graft rejection, posterior sacroiliac ligament graft rejection, sacrotuberous ligament graft rejection, sacrospinous ligament graft rejection, inferior pubic ligament graft rejection, superior pubic ligament graft rejection, anterior cruciate ligament graft rejection, lateral collateral ligament graft rejection, posterior cruciate ligament graft rejection, medial collateral ligament graft rejection, cranial cruciate ligament graft rejection, caudal cruciate ligament graft rejection, and patellar ligament graft rejection. In some embodiments, the organ graft rejection is selected from the group consisting of heart graft rejection, lung graft rejection, kidney graft rejection, liver graft rejection, pancreas graft rejection, intestine graft rejection, and thymus graft rejection.

[0136] In some embodiments, the method is for treating a graft-versus-host disease in the human subject. In some embodiments, the graft-versus-host disease arises from a bone marrow transplant, or one or more blood cells selected from the group consisting of hematopoietic stem cells, common myeloid progenitor cells, common lymphoid progenitor cells, megakaryocytes, monocytes, basophils, eosinophils, neutrophils, macrophages, T cells, B cells, natural killer cells, and dendritic cells.

[0137] In some embodiments, the method is for transplantation or for regenerating a tissue or organ in the human subject. In some embodiments, the tissue or organ is selected from the group consisting of pancreas, islets, salivary gland, pituitary gland, kidney, heart, lung, hematopoietic system, cranial nerves, heart, aorta, olfactory gland, ear, nerve, eye, thymus, tongue, bone, liver, small intestine, large intestine, gastrointestinal, lung, brain, skin, peripheral nervous system, central nervous system, spinal cord, breast, embryonic structures, embryo, and testes. In some embodiments, the tissue or organ expresses the TNFRSF member protein, the TNFSF member protein, CD28, or ICOS.

[0138] In a ninth aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds to a human TNFRSF member protein, in which the antibody or antigen-binding fragment thereof comprises at least 50 amino acid residues of an Fc domain and one or more amino acid substitutions within the Fc domain, further in which:

[0139] (a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0140] (i) L235E;

[0141] (ii) L234A and L235A;

[0142] (iii) L234A, L235A, and P329G (iv) L234E, L235F, and P331 S;

[0143] (v) D265A;

[0144] (vi) G237A;

[0145] (vii) E318A;

[0146] (viii) E233P

[0147] (ix) G236R and L328R;

[0148] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0149] (xi) N297G or N297Q;

[0150] (b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0151] (i) D265A;

[0152] (ii) G237A;

[0153] (iii) E318A;

[0154] (iv) H268Q, V309L, A330S, and P331 S;

[0155] (v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and

[0156] (vi) N297G or N297Q;

[0157] (c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0158] (i) L235E;

[0159] (ii) L234A and L235A;

[0160] (iii) L234A, L235A, and P329G

[0161] (iv) L234E, L235F, and P331 S;

[0162] (v) D265A;

[0163] (vi) G237A;

[0164] (vii) E318A;

[0165] (viii) E233P

[0166] (ix) G236R and L328R;

[0167] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0168] (xi) N297G or N297Q;

[0169] (d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0170] (i) L235E;

[0171] (ii) D265A;

[0172] (iii) G237A;

[0173] (iv) E318A;

[0174] (v) E233P

[0175] (vi) G236R and L328R; and (vii) N297G or N297Q; or

[0176] (e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P (S241 P according to Kabat), the Fc domain is a human lgG4 Fc domain, and, optionally, the one or more amino acid substitutions are selected from the group consisting of:

[0177] (i) L235E; and

[0178] (ii) F234A and L235A, and in which the amino acid positions are numbered according to the EU index. In some embodiments, the antibody or antigen-binding fragment thereof is an lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the amino acid substitution S228P.

[0179] In some embodiments, the TNFRSF member protein is selected from the group consisting of TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3. In some embodiments, the TNFRSF member protein is TNFR2.

[0180] In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

[0181] In some embodiments, the TNFRSF member protein is TNFR2. In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR-H1 comprising the amino acid sequence of X1X2X2X1X2X3X2JJJ, in which each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently Y, S, T, C, N, or Q; X3is D or E; and each J is independently a naturally occurring amino acid or is absent. In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTZ1Z2JJJ (SEQ ID NO: 1480), in which Z1is D or T; Z2is Y, F, or L; and each J is independently a naturally occurring amino acid or is absent. In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0182] In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR-H1 comprising the amino acid sequence of X1X2X2X3X1, in which each X1is independently D or E; each X2is independently Y, S, T, C, N, or Q; and X3is L, A, V, G, I, M, W, F, or P. In some embodiments, the CDR-H1 comprises the amino acid sequence of DYNLD (SEQ ID NO: 1541 ). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0183] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-H2 comprising the amino acid sequence of X1X2X3X2X3X3X1X3X3X3X3X3X3X4X2X4X2, in which each X1is independently D or E; each X2is independently I, A, V, L, G, M, W, F, or P; each X3is independently N, S, T, C, Y, or Q; and each X4is independently K, R, or H. In some embodiments, the CDR-H2 comprises the amino acid sequence of DINPNYDSTSYSQKFRG (SEQ ID NO: 1542). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0184] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-H3 comprising the amino acid sequence of X1X2X2X1X2X1X3X1, in which each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently N, S, T, C, Y, or Q; and X3is D or E. In some embodiments, the CDR-H3 comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1543). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0185] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-L1 comprising the amino acid sequence of X1X2X1X1X1X2X3X4X1X1, in which each X1is independently S, Y, T, C, N, or Q; each X2is independently A, G, V, L, I, M, W, F, or P; X3is R, H, or K; and X4is Y, A, V, I, L, M, F, or W. In some embodiments, the CDR-L1 comprises the amino acid sequence of SASSSVRYNY (SEQ ID NO: 1544). In some embodiments, the antibody or antigenbinding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR- L2, and a CDR-L3 set forth in Table 2.

[0186] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-L2 comprising the amino acid sequence of X1X2X2X2X1X1X2, in which each X1is independently L, A, V, G, I, M, W, F, or P; and each X2is independently T, S, C, Y, N, or Q. In some embodiments, the CDR-L2 comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1545). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , and a CDR-L3 set forth in Table 2.

[0187] In some embodiments, the modified antibody or antigen-binding fragment thereof comprises a CDR-L3 comprising the amino acid sequence of X1X2X2X1X2X2X2X1X1X2, in which each X1is independently P, A, V, L, I, M, W, F, or G; and each X2is independently Q, S, T, C, N, or Y. In some embodiments, the CDR-L3 comprises the amino acid sequence of PQQWSSNPLT (SEQ ID NO: 1546). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , and a CDR-L2 set forth in Table 2.

[0188] In some embodiments, the antibody or antigen-binding fragment thereof comprises a CORFU , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the sequences set forth in Table 3.

[0189] In some embodiments, the TNFRSF member protein is selected from the group consisting of CD27, CD40, GITR, 0X40, and 4-1 BB. In some embodiments, the antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of an antibody selected from the group consisting of varlilumab (CDX-1127), CDX-1140, SEA-CD40, R07009789, JNJ-64457107 (ADC1013), APX-005M, Chi Lob 7 / 4, TRX-518, MK-4166, MK-1248, GWN-323, INCAGN01876, BMS-986156, AMG-228, tavolimab (MEDI0562), PF-04518600, BMS-986178, MOXR-0916, GSK-3174998, INCAGN01949, utomilumab (PF-05082566), and urelumab (BMS-663513). In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of an antibody selected from the group consisting of varlilumab (CDX-1127), CDX- 1140, SEA-CD40, RG7009789, JNJ-64457107 (ADC1013), APX-005M, Chi Lob 7 / 4, TRX-518, MK- 4166, MK-1248, GWN-323, INCAGN01876, BMS-986156, AMG-228, tavolimab (MEDI0562), PF- 04518600, BMS-986178, MOXR-0916, GSK-3174998, INCAGN01949, utomilumab (PF-05082566), and urelumab (BMS-663513).

[0190] In some embodiments, the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

[0191] In some embodiments, the TNFRSF member protein is TNFR2. In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 4. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the sequences set forth in Table 5.

[0192] In some embodiments, the antibody or antigen-binding fragment thereof is neither an agonist nor an antagonist of the TNFRSF member protein. In some embodiments, the TNFRSF member protein is TNFR2. In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 6. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the sequences set forth in Table 7.

[0193] In some embodiments, the antibody or antigen-binding fragment thereof has less than 90% (e.g., less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%) cross-reactivity with the soluble TNFRSF member protein. In some embodiments, the antibody or antigen-binding fragment thereof has less than 50% cross-reactivity with the soluble TNFRSF member protein.

[0194] In a tenth aspect, the disclosure features an agonistic antibody or antigen-binding fragment thereof that specifically binds human TNFR2, comprising:

[0195] (A) means for binding an epitope within human TNFR2, comprising:

[0196] (a) a CDR-H1 comprising the amino acid sequence of: (i) X1X2X2X1X2X3X2JJJ, in which each X1is independently G, A, V, L, I,

[0197] M, W, F, or P; each X2is independently Y, S, T, C, N, or Q; X3is D or E; and each J is independently a naturally occurring amino acid or is absent; or

[0198] (ii) X1X2X2X3X1, in which each X1is independently D or E; each X2is independently Y, S, T, C, N, or Q; and X3is L, A, V, G, I, M, W, F, or P;

[0199] (b) a CDR-H2 comprising the amino acid sequence of X1X2X3X2X3X3X1X3X3X3X3X3X3X4X2X4X2, in which each X1 is independently D or E; each X2 is independently I, A, V, L, G, M, W, F, or P; each X3is independently N, S, T, C, Y, or Q; and each X4 is independently K, R, or H;

[0200] (c) a CDR-H3 comprising the amino acid sequence of X1X2X2X1X2X1X3X1, in which each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently N, S, T, C, Y, or Q; and X3is D or E;

[0201] (d) a CDR-L1 comprising the amino acid sequence of X1X2X1X1X1X2X3X4X1X1, in which each X1is independently S, Y, T, C, N, or Q; each X2is independently A, G, V, L, I, M, W, F, or P; X3is R, H, or K; and X4is Y, A, V, I, L, M, F, or W;

[0202] (e) a CDR-L2 comprising the amino acid sequence of X1X2X2X2X1X1X2, in which each X1is independently L, A, V, G, I, M, W, F, or P; and each X2is independently T, S, C, Y, N, or Q; and / or

[0203] (f) a CDR-L3 comprising the amino acid sequence of X1X2X2X1X2X2X2X1X1X2, in which each X1is independently P, A, V, L, I, M, W, F, or G; and each X2is independently Q, S, T, C, N, or Y; and

[0204] (B) an Fc domain comprising one or more amino acid substitutions, in which:

[0205] (a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0206] (i) L235E;

[0207] (ii) L234A and L235A;

[0208] (iii) L234A, L235A, and P329G

[0209] (iv) L234E, L235F, and P331 S;

[0210] (v) D265A;

[0211] (vi) G237A;

[0212] (vii) E318A;

[0213] (viii) E233P

[0214] (ix) G236R and L328R;

[0215] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0216] (xi) N297G or N297Q; (b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0217] (i) D265A;

[0218] (ii) G237A;

[0219] (iii) E318A;

[0220] (iv) H268Q, V309L, A330S, and P331 S;

[0221] (v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and

[0222] (vi) N297G or N297Q;

[0223] (c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0224] (i) L235E;

[0225] (ii) L234A and L235A;

[0226] (iii) L234A, L235A, and P329G

[0227] (iv) L234E, L235F, and P331 S;

[0228] (v) D265A;

[0229] (vi) G237A;

[0230] (vii) E318A;

[0231] (viii) E233P

[0232] (ix) G236R and L328R;

[0233] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0234] (xi) N297G or N297Q;

[0235] (d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0236] (i) L235E;

[0237] (ii) D265A;

[0238] (iii) G237A;

[0239] (iv) E318A;

[0240] (v) E233P

[0241] (vi) G236R and L328R; and

[0242] (vii) N297G or N297Q; or

[0243] (e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P (S241 P according to Kabat), the Fc domain is a human lgG4 Fc domain, and, optionally, the one or more amino acid substitutions are selected from the group consisting of:

[0244] (i) L235E; and

[0245] (ii) F234A and L235A, and in which the amino acid positions are numbered according to the EU index. In some embodiments, the antibody or antigen-binding fragment thereof is an lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the amino acid substitution S228P.

[0246] In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTZ1Z2JJJ (SEQ ID NO: 1480), in which Z1is D or T; Z2is Y, F, or L; and each J is independently a naturally occurring amino acid or is absent. In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413). In some embodiments, the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0247] In an eleventh aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds to a human TNFSF member protein, in which the antibody or antigen-binding fragment thereof comprises at least 50 amino acid residues of an Fc domain and one or more amino acid substitutions within the Fc domain, further in which:

[0248] (a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0249] (i) L235E;

[0250] (ii) L234A and L235A;

[0251] (iii) L234A, L235A, and P329G

[0252] (iv) L234E, L235F, and P331 S;

[0253] (v) D265A;

[0254] (vi) G237A;

[0255] (vii) E318A;

[0256] (viii) E233P

[0257] (ix) G236R and L328R;

[0258] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0259] (xi) N297G or N297Q;

[0260] (b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0261] (i) D265A;

[0262] (ii) G237A;

[0263] (iii) E318A;

[0264] (iv) H268Q, V309L, A330S, and P331 S;

[0265] (v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and

[0266] (vi) N297G or N297Q;

[0267] (c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0268] (i) L235E; (ii) L234A and L235A;

[0269] (iii) L234A, L235A, and P329G

[0270] (iv) L234E, L235F, and P331 S;

[0271] (v) D265A;

[0272] (vi) G237A;

[0273] (vii) E318A;

[0274] (viii) E233P

[0275] (ix) G236R and L328R;

[0276] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0277] (xi) N297G or N297Q;

[0278] (d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0279] (i) L235E;

[0280] (ii) D265A;

[0281] (iii) G237A;

[0282] (iv) E318A;

[0283] (v) E233P

[0284] (vi) G236R and L328R; and

[0285] (vii) N297G or N297Q; or

[0286] (e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P (S241 P according to Kabat), the Fc domain is a human lgG4 Fc domain, and, optionally, the one or more amino acid substitutions are selected from the group consisting of:

[0287] (i) L235E; and

[0288] (ii) F234A and L235A, and in which the amino acid positions are numbered according to the EU index.

[0289] In some embodiments, the antibody or antigen-binding fragment thereof is an lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the amino acid substitution S228P.

[0290] In some embodiments, the TNFSF member protein is TRAIL.

[0291] In a twelfth aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds to human CD28, in which the antibody or antigen-binding fragment thereof comprises at least 50 amino acid residues of an Fc domain and one or more amino acid substitutions within the Fc domain, further in which:

[0292] (a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0293] (i) L235E; (ii) L234A and L235A;

[0294] (iii) L234A, L235A, and P329G

[0295] (iv) L234E, L235F, and P331 S;

[0296] (v) D265A;

[0297] (vi) G237A;

[0298] (vii) E318A;

[0299] (viii) E233P

[0300] (ix) G236R and L328R;

[0301] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0302] (xi) N297G or N297Q;

[0303] (b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0304] (i) D265A;

[0305] (ii) G237A;

[0306] (iii) E318A;

[0307] (iv) H268Q, V309L, A330S, and P331 S;

[0308] (v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and

[0309] (vi) N297G or N297Q;

[0310] (c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0311] (i) L235E;

[0312] (ii) L234A and L235A;

[0313] (iii) L234A, L235A, and P329G

[0314] (iv) L234E, L235F, and P331 S;

[0315] (v) D265A;

[0316] (vi) G237A;

[0317] (vii) E318A;

[0318] (viii) E233P

[0319] (ix) G236R and L328R;

[0320] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0321] (xi) N297G or N297Q;

[0322] (d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0323] (i) L235E;

[0324] (ii) D265A;

[0325] (iii) G237A;

[0326] (iv) E318A; (v) E233P

[0327] (vi) G236R and L328R; and

[0328] (vii) N297G or N297Q; or

[0329] (e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P (S241 P according to Kabat), the Fc domain is a human lgG4 Fc domain, and, optionally, the one or more amino acid substitutions are selected from the group consisting of:

[0330] (i) L235E; and

[0331] (ii) F234A and L235A, and in which the amino acid positions are numbered according to the EU index.

[0332] In some embodiments, the antibody or antigen-binding fragment thereof is an lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the amino acid substitution S228P.

[0333] In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds CD28. In some embodiments, the antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of theralizumab (TAB-08). In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and the VL sequences of theralizumab (TAB-08).

[0334] In a thirteenth aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds to human ICOS, in which the antibody or antigen-binding fragment thereof comprises at least 50 amino acid residues of an Fc domain and one or more amino acid substitutions within the Fc domain, further in which:

[0335] (a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0336] (i) L235E;

[0337] (ii) L234A and L235A;

[0338] (iii) L234A, L235A, and P329G

[0339] (iv) L234E, L235F, and P331 S;

[0340] (v) D265A;

[0341] (vi) G237A;

[0342] (vii) E318A;

[0343] (viii) E233P

[0344] (ix) G236R and L328R;

[0345] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0346] (xi) N297G or N297Q; (b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0347] (i) D265A;

[0348] (ii) G237A;

[0349] (iii) E318A;

[0350] (iv) H268Q, V309L, A330S, and P331 S;

[0351] (v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and

[0352] (vi) N297G or N297Q;

[0353] (c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0354] (i) L235E;

[0355] (ii) L234A and L235A;

[0356] (iii) L234A, L235A, and P329G

[0357] (iv) L234E, L235F, and P331 S;

[0358] (v) D265A;

[0359] (vi) G237A;

[0360] (vii) E318A;

[0361] (viii) E233P

[0362] (ix) G236R and L328R;

[0363] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0364] (xi) N297G or N297Q;

[0365] (d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:

[0366] (i) L235E;

[0367] (ii) D265A;

[0368] (iii) G237A;

[0369] (iv) E318A;

[0370] (v) E233P

[0371] (vi) G236R and L328R; and

[0372] (vii) N297G or N297Q; or

[0373] (e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P (S241 P according to Kabat), the Fc domain is a human lgG4 Fc domain, and, optionally, the one or more amino acid substitutions are selected from the group consisting of:

[0374] (i) L235E; and

[0375] (ii) F234A and L235A, and in which the amino acid positions are numbered according to the EU index. In some embodiments, the antibody or antigen-binding fragment thereof is an lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the amino acid substitution S228P.

[0376] In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds ICOS. In some embodiments, the antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of GSK-3359609 or JTX-2011 . In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and the VL sequences of GSK-3359609 or JTX-2011 .

[0377] In some embodiments, the antibody or antigen-binding fragment thereof does not comprise any one of the amino acid substitutions set forth in Table 18, and in which the amino acid positions are numbered according to the EU index.

[0378] In some embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, and a chimeric antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is a human, humanized, or chimeric antibody or antigen-binding fragment thereof.

[0379] In a fourteenth aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds to a human TNFRSF member protein, a human TNFSF member protein, human CD28, or human ICOS, in which the antibody or antigen-binding fragment thereof does not comprise an Fc domain.

[0380] In some embodiments, the TNFRSF member protein is selected from the group consisting of TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3. In some embodiments, the TNFRSF member protein is TNFR2.

[0381] In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2. In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the sequences set forth in Table 3.

[0382] In some embodiments, the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2. In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 4. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the sequences set forth in Table 5.

[0383] In some embodiments, the TNFSF member protein is TRAIL.

[0384] In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds CD28. In some embodiments, the antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of theralizumab (TAB-08). In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and the VL sequences of theralizumab (TAB-08).

[0385] In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds ICOS. In some embodiments, the antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of GSK-3359609 or JTX-2011 . In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and the VL sequences of GSK-3359609 or JTX-2011 .

[0386] In some embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of a single-chain Fv molecule (scFv), a diabody, a triabody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab’)2 molecule, and a tandem scFv (taFv).

[0387] In a fifteenth aspect, the disclosure features methods of producing the antibody or antigenbinding fragment thereof disclosed in the ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth aspect of the disclosure, the method comprising expressing a polynucleotide encoding the antibody or antigen-binding fragment thereof in a host cell and recovering the antibody or antigen-binding fragment thereof from host cell medium.

[0388] In a sixteenth aspect, the disclosure features constructs comprising a first polypeptide domain and a second polypeptide domain, in which the first polypeptide domain and the second polypeptide domain are each, independently, an antigen-binding fragment disclosed in the ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth aspect of the disclosure. In some embodiments, the first polypeptide domain and the second polypeptide domain are bound by a covalent linker. In some embodiments, the covalent linker comprises an amide bond or a disulfide bond.

[0389] In a seventeenth aspect, the disclosure features polynucleotides encoding the antibody or antigen-binding fragment thereof disclosed in the ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth aspect of the disclosure or the construct disclosed in the sixteenth aspect of the disclosure.

[0390] In an eighteenth aspect, the disclosure features vectors comprising the polynucleotide disclosed in the seventeenth aspect of the disclosure.

[0391] In some embodiments, the vector is an expression vector. In some embodiments, the expression vector is a eukaryotic expression vector.

[0392] In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is selected from the group consisting of an adenovirus, retrovirus, poxvirus, adeno-associated virus, baculovirus, herpes simplex virus, and vaccinia virus. In some embodiments, the adenovirus is a serotype 1 -60 adenovirus. In some embodiments, the adenovirus is a serotype 5, 26, 35, or 48 adenovirus. In some embodiments, the retrovirus is a y-retrovirus or a lentivirus. In some embodiments, the vaccinia virus is a modified vaccinia Ankara (MVA).

[0393] In an nineteenth aspect, the disclosure features isolated host cells comprising the vector disclosed in the eighteenth aspect of the disclosure.

[0394] In some embodiments, the host cell is a prokaryotic cell or a eukaryotic cell. In some embodiments, the eukaryotic cell is a mammalian cell. In some embodiments, the mammalian cell is a CHO cell.

[0395] In a twentieth aspect, the disclosure features pharmaceutical compositions comprising the antibody or antigen-binding fragment thereof disclosed in the ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth aspect of the disclosure, the construct disclosed in the sixteenth aspect of the disclosure, the polynucleotide disclosed in the seventeenth aspect of the disclosure, the vector disclosed in the eighteenth aspect of the disclosure, or the host cell disclosed in the nineteenth aspect of the disclosure, and a pharmaceutically acceptable carrier or excipient.

[0396] In a twenty-first aspect, the disclosure features methods of modulating an immune response in a human subject, the method comprising administering to the subject the antibody or antigenbinding fragment thereof disclosed in the ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth aspect of the disclosure, the construct disclosed in the sixteenth aspect of the disclosure, the polynucleotide disclosed in the seventeenth aspect of the disclosure, the vector disclosed in the eighteenth aspect of the disclosure, the host cell disclosed in the nineteenth aspect of the disclosure, or the pharmaceutical composition disclosed in the twentieth aspect of the disclosure.

[0397] In some embodiments, the method is for treating a cell proliferation disorder, an autoimmune disease, an infectious disease, an inflammatory disease, a neurological disease, an allergy, a transplant rejection (e.g., an allograft rejection), or a graft-versus-host disease in the human subject. In some embodiments, the method is for transplantation or for regenerating a tissue or organ in the human subject.

[0398] In some embodiments, the cell proliferation disorder is a cancer. In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein selected from the group consisting of TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TNFR1 , Fas, CD40, CD27, 4-1 BB, 0X40, GITR, and XEDAR. In some embodiments, the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein selected from the group consisting of TRAMP, NGFR, TRAIL-R4, TNFR2, HVEM, CD30, TROY, and RELT.

[0399] In some embodiments, the human subject has a serum or plasma level of a soluble TNFRSF member protein that is lower than or the same as a reference level of the soluble TNFRSF member protein, and the method comprising administering to the subject an agonistic antibody or antigenbinding fragment thereof that specifically binds the TNFRSF member protein. In some embodiments, the human subject has a serum or plasma level of a soluble TNFRSF member protein that is higher than a reference level of the soluble TNFRSF member protein, and the method comprising administering to the subject an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

[0400] In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein of the disclosure is administered to human subject at a low dose. In some instances, the low dose is a dose level that is lower than, e.g., a typical (or art-recognized) dose level of a corresponding antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is administered once every week at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg (e.g., about 0.8 mg / kg, about 0.85 mg / kg, about 0.9 mg / kg, about 0.95 mg / kg, about 1 .0 mg / kg, about 1 .05 mg / kg, about 1 .1 mg / kg, about 1 .15 mg / kg, or about 1 .2 mg / kg). In some embodiments, the antibody or antigen-binding fragment thereof is administered once every two weeks at a dose of from about 1 .65 mg / kg to about 2.5 mg / kg (e.g., about 1 .65 mg / kg, about 1 .7 mg / kg, about 1 .75 mg / kg, about 1 .8 mg / kg, about 1 .85 mg / kg, about 1 .9 mg / kg, about 1 .95 mg / kg, about 2.0 mg / kg, about 2.05 mg / kg, about 2.1 mg / kg, about 2.15 mg / kg, about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, or about 2.5 mg / kg). In some embodiments, the antibody or antigen-binding fragment thereof is administered once every three weeks at a dose of from about 2.2 mg / kg to about 3.0 mg / kg (e.g., about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, about 2.5 mg / kg, about 2.55 mg / kg, about 2.6 mg / kg, about 2.65 mg / kg, about 2.7 mg / kg, about 2.75 mg / kg, about 2.8 mg / kg, about 2.85 mg / kg, about 2.9 mg / kg, about 2.95 mg / kg, or about 3.0 mg / kg). In some embodiments, the antibody or antigen-binding fragment thereof is administered once every four weeks at a dose of from about 2.5 mg / kg to about 4.2 mg / kg (e.g., about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, or about 4.2 mg / kg).

[0401] In a twenty-second aspect, the disclosure features kits comprising an agent selected from the group consisting of the antibody or antigen-binding fragment thereof disclosed in the ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth aspect of the disclosure, the construct disclosed in the sixteenth aspect of the disclosure, the polynucleotide disclosed in the seventeenth aspect of the disclosure, the vector disclosed in the eighteenth aspect of the disclosure, the host cell disclosed in the nineteenth aspect of the disclosure, or the pharmaceutical composition disclosed in the twentieth aspect of the disclosure.

[0402] In some embodiments, the kit further comprises instructions for transfecting the vector into a host cell. In some embodiments, the kit further comprises instructions for expressing the antibody or antigen-binding fragment thereof or the construct in a host cell. In some embodiments, the kit further comprises a reagent that can be used to express the antibody or antigen-binding fragment thereof or the construct in a host cell. In some embodiments, the kit further comprises instructions for administering the agent to a human subject. In some embodiments, the kit further comprises instructions for making or using the agent. In some embodiments, the kit further comprises instructions for determining a level of the soluble TNFRSF member protein.

[0403] In a twenty-third aspect, the disclosure features methods comprising:

[0404] (a)

[0405] (i) detecting a level of a soluble TNFRSF member protein in a biological fluid from a subject, in which the level of the soluble TNFRSF member protein in the biological fluid is higher (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) relative to a reference level of the soluble TNFRSF member protein; and

[0406] (ii) administering to the subject one or more doses of an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein at a dosing frequency, wherein the method is for decreasing the level of the soluble TNFRSF member protein; or

[0407] (b)

[0408] (i) detecting a level of a soluble TNFRSF member protein in a biological fluid from a subject, in which the level of the soluble TNFRSF member protein in the biological fluid is normal or lower (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) relative to a reference level of the soluble TNFRSF member protein; and

[0409] (ii) administering to the subject one or more doses of an agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein at a dosing frequency, wherein the method is for augmenting the level of the soluble TNFRSF member protein.

[0410] In some embodiments, the normal level of the soluble TNFRSF member protein in a biological fluid is the level of the soluble TNFRSF member protein in the biological fluid (e.g., serum or plasma) of an otherwise healthy human. In some embodiments, the normal level of soluble TNFR2 in the serum of a human subject is from about 1 .53 ng / ml to about 3.00 ng / ml (e.g., from about 1 .80 ng / ml to about 3.00 ng / ml, from about 2.10 ng / ml to about 3.00 ng / ml, from about 2.40 ng / ml to about 3.00 ng / ml, from about 2.70 ng / ml to about 3.00 ng / ml, from about 1 .53 ng / ml to about 2.70 ng / ml, from about 1 .80 ng / ml to about 2.70 ng / ml, from about 2.10 ng / ml to about 2.70 ng / ml, from about 2.40 ng / ml to about 2.70 ng / ml, from about 1 .53 ng / ml to about 2.40 ng / ml, from about 1 .80 ng / ml to about 2.40 ng / ml, from about 2.10 ng / ml to about 2.40 ng / ml, from about 1 .53 ng / ml to about 2.10 ng / ml, from about 1 .80 ng / ml about 2.10 ng / ml, from about 1 .53 ng / ml to about 1 .80 ng / ml, about 1 .53 ng / ml, about 1 .80 ng / ml, about 2.10 ng / ml, about 2.40 ng / ml, about 2.70 ng / ml, or about 3.00 ng / ml). In some embodiments, the augmented level of the soluble TNFRSF member protein in a biological fluid is higher (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) than the normal level of the soluble TNFRSF member protein in the biological fluid. In some embodiments, the augmented level of soluble TNFR2 in the serum of a human subject is from about 2.53 ng / ml to about 10 ng / ml (e.g., from about 2.53 ng / ml to about 3 ng / ml, from about 2.53 ng to about 4 ng / ml, from about 2.53 ng to about 6 ng / ml, from about 2.53 ng to about 8 ng / ml, from about 3 ng / ml to about 4 ng / ml, from about 3 ng / ml to about 6 ng / ml, from about 3 ng / ml to about 8 ng / ml, from about 3 ng / ml to about 10 ng / ml, from about 4 ng / ml to about 6 ng / ml, from about 4 ng / ml to about 8 ng / ml, from about 4 ng / ml to about 10 ng / ml, from about 6 ng / ml to about 8 ng / ml, from about 6 ng / ml to about 10 ng / ml, from about 8 ng / ml to about 10 ng / ml, about 2.53 ng / ml, about 3 ng / ml, about 4 ng / ml, about 6 ng / ml, about 8 ng / ml, or about 10 ng / ml). When the level of the soluble TNFRSF member protein in the human subject is higher (e.g., by 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) than the normal level of soluble TNFRSF member protein, an antagonistic antibody or antigen-binding fragment thereof that specifically binds the corresponding TNFRSF member protein may be used to lower the level of the soluble TNFRSF member protein in the human subject (e.g., to the normal level of the soluble TNFRSF member protein).

[0411] In some embodiments, the decreased (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) level of the soluble TNFRSF member protein in the human subject indicates the presence of inadequate T cell suppression and the need for more TNFR2 function such as a cell proliferation disorder, an autoimmune disease, an infectious disease, an inflammatory disease, a neurological disease, an allergy, a transplant rejection (e.g., an allograft rejection), or a graft-versus-host disease in the human subject. In some embodiments, the neurological disease is Alzheimer’s disease. In this case, a corresponding TNFRSF agonist (an agonistic antibody or antigen-binding fragment thereof that binds the TNFRSF member protein corresponding to the soluble TNFRSF member protein, such as the agonistic antibodies or antigen-binding fragments disclosed herein) can be used to increase the level of the soluble TNFRSF member protein. This strategy can be used in the screening for antibodies, in clinical trials to determine optimal dosing levels of TNFRSF agonists, or in clinical practice to make sure the dosing levels of TNFRSF agonists administered to a subject are therapeutically effective. For example, lowered levels of soluble TNFR2 in a human subject may indicate a flare of autoimmunity or impending transplant rejection. Increased levels of soluble TNFR2 in a human subject may indicate cancer with a Treg- and / or TNFR2-driven mechanism in need of a therapy to lower soluble TNFR2 levels (e.g., by eliminating suppressor cells such as Treg cells or MDSCs). In organ or tissue transplantation, the host may have a normal level of soluble TNFR2, but the desire would be to elevate the level of soluble TNFR2 (e.g., by administering to the host a TNFR2 agonist, such as an agonistic antibody that binds TNFR2 as described herein) to maintain the viability of the transplanted organ or tissue by promoting Treg cellular activity.

[0412] In some embodiments, the method comprises detecting a normal level of the soluble TNFRSF member protein or an increased (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) level of the soluble TNFRSF member protein in a biological fluid of the subject relative to a reference level of the soluble TNFRSF member protein, in which the method further comprises changing (e.g., increasing or decreasing) the dosage and / or dosing frequency of the antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein. In some embodiments, the antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein decreases or increases (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) the level of the TNFRSF member protein. In a preferred embodiment, the antagonistic antibody or antigenbinding fragment thereof that specifically binds the TNFRSF member protein decreases (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) the level of the TNFRSF member protein.

[0413] In some embodiments, the method comprises detecting a normal level of the soluble TNFRSF member protein or an decreased (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) level of the soluble TNFRSF member protein in a biological fluid of the subject relative to a reference level of the soluble TNFRSF member protein, in which the method further comprises changing (e.g., increasing or decreasing) the dosage and / or dosing frequency of the agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein. In some embodiments, the agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein decreases or increases (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) the level of the TNFRSF member protein. In a preferred embodiment, the agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein increases (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) the level of the TNFRSF member protein.

[0414] In some embodiments, the method comprises detecting an increased (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) level of the soluble TNFRSF member protein in a biological fluid of the subject relative to a reference level of the soluble TNFRSF member protein, in which the method further comprises:

[0415] (a) increasing the dosage and / or dosing frequency of the antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein; or

[0416] (b) decreasing the dosage and / or dosing frequency of the agonistic antibody or antigenbinding fragment thereof that specifically binds the TNFRSF member protein.

[0417] In some embodiments, the method comprises detecting a normal or decreased (e.g., by 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) level of the soluble TNFRSF member protein in a biological fluid of the subject relative to a reference level of the soluble TNFRSF member protein, in which the method further comprises:

[0418] (a) increasing the dosage and / or dosing frequency of the agonistic antibody or antigenbinding fragment thereof that specifically binds the TNFRSF member protein; or

[0419] (b) decreasing the dosage and / or dosing frequency of the antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

[0420] In some embodiments, the TNFRSF member protein is selected from the group consisting of TNFR2, 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TNFR1 , TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3. In some embodiments, the TNFRSF member protein is TNFR2.

[0421] In some embodiments, the antagonistic or agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein is administered to the human subject at a dosing frequency of once every week, once every two weeks, once every three weeks, or once every four weeks.

[0422] In some embodiments, the antagonistic or agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein is administered to the human subject at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg (e.g., about 0.8 mg / kg, about 0.85 mg / kg, about 0.9 mg / kg, about 0.95 mg / kg, about 1 .0 mg / kg, about 1 .05 mg / kg, about 1 .1 mg / kg, about 1 .15 mg / kg, or about 1 .2 mg / kg), from about 1 .65 mg / kg to about 2.5 mg / kg (e.g., about 1 .65 mg / kg, about 1 .7 mg / kg, about 1 .75 mg / kg, about 1 .8 mg / kg, about 1 .85 mg / kg, about 1 .9 mg / kg, about 1 .95 mg / kg, about 2.0 mg / kg, about 2.05 mg / kg, about 2.1 mg / kg, about 2.15 mg / kg, about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, or about 2.5 mg / kg), from about 2.2 mg / kg to about 3.0 mg / kg (e.g., about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, about 2.5 mg / kg, about 2.55 mg / kg, about 2.6 mg / kg, about 2.65 mg / kg, about 2.7 mg / kg, about 2.75 mg / kg, about 2.8 mg / kg, about 2.85 mg / kg, about 2.9 mg / kg, about 2.95 mg / kg, or about 3.0 mg / kg), or from about 2.5 mg / kg to about 4.2 mg / kg (e.g., about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, or about 4.2 mg / kg).

[0423] In some embodiments, the antagonistic or agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein is administered to the human subject:

[0424] (a) once every week at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg (e.g., about 0.8 mg / kg, about 0.85 mg / kg, about 0.9 mg / kg, about 0.95 mg / kg, about 1 .0 mg / kg, about 1 .05 mg / kg, about 1 .1 mg / kg, about 1.15 mg / kg, or about 1 .2 mg / kg);

[0425] (b) once every two weeks at a dose of from about 1 .65 mg / kg to about 2.5 mg / kg (e.g., about 1 .65 mg / kg, about 1 .7 mg / kg, about 1 .75 mg / kg, about 1 .8 mg / kg, about 1 .85 mg / kg, about 1 .9 mg / kg, about 1 .95 mg / kg, about 2.0 mg / kg, about 2.05 mg / kg, about 2.1 mg / kg, about 2.15 mg / kg, about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, or about 2.5 mg / kg);

[0426] (c) once every three weeks at a dose of from about 2.2 mg / kg to about 3.0 mg / kg (e.g., about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, about 2.5 mg / kg, about 2.55 mg / kg, about 2.6 mg / kg, about 2.65 mg / kg, about 2.7 mg / kg, about 2.75 mg / kg, about 2.8 mg / kg, about 2.85 mg / kg, about 2.9 mg / kg, about 2.95 mg / kg, or about 3.0 mg / kg); or

[0427] (d) once every four weeks at a dose of from about 2.5 mg / kg to about 4.2 mg / kg (e.g., about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, or about 4.2 mg / kg).

[0428] In some embodiments, the method further comprises decreasing the dose range of the antagonistic or the agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

[0429] In some embodiments, the antagonistic or agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein is administered to the human subject subcutaneously. In some embodiments, the level of soluble TNFR2 in a human subject is the serum or plasma level of soluble TNFR2 in the human subject. In some embodiments, the burden (e.g., cell number) of Treg cells or MDSCs (e.g., TNFR2-expressing Treg cells or MDSCs) is measured directly in the tumor microenvironment of a human subject having cancer.

[0430] In some embodiments, the method is for treating a cell proliferation disorder, an autoimmune disease, an infectious disease, an inflammatory disease, a neurological disease, an allergy, a transplant rejection (e.g., an allograft rejection), or a graft-versus-host disease in the human subject. In some embodiments, the method is for transplantation or for regenerating a tissue or organ in the human subject. In some embodiments, the method is for treating a cell proliferation disorder, and the antibody or antigen-binding fragment thereof is an antagonist antibody or antigen-binding fragment thereof that specifically binds TRAMP, DR6, NGFR, RANK, FN14, TNFR2, LT-p receptor, HVEM, CD30, BCMA, TACI, BAFF, TROY, or RELT. In some embodiments, the method is for treating a cell proliferation disorder, and the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds TRAIL-R1 , TRAIL-R2, TRAIL-R3, TRAIL-R4, TNFR1 , Fas, CD40, CD27, 4-1 BB, 0X40, GITR, or XEDAR. In some embodiments, the method is for treating an autoimmune disease, and the antibody or antigen-binding fragment thereof is an antagonist antibody or antigen-binding fragment thereof that specifically binds TRAIL-R1 , TRAIL-R2, TRAIL-R3, TRAIL-R4, TNFR1 , CD40, CD27, 4-1 BB, 0X40, GITR, or XEDAR. In some embodiments, the method is for treating an autoimmune disease, and the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds TRAMP, DR6, NGFR, FN14, TNFR2, LT-p receptor, HVEM, CD30, or RELT. In some embodiments, the method is for treating an infectious disease, and the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TRAMP, DR6, TNFR2, HVEM, or RELT. In some embodiments, the method is for treating an infectious disease, and the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds TRAIL-R1 , TRAIL-R2, TRAIL-R3, TRAIL-R4, CD40, CD27, 4-1 BB, 0X40, BCMA, TACI, or BAFF. In some embodiments, the method is for treating an inflammatory disease, and the antibody or antigen-binding fragment thereof is an agonistic antibody or antigenbinding fragment thereof that specifically binds DR6, FN14, TNFR2, HVEM, or RELT. In some embodiments, the method is for treating a neurological disease, and the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds DR6. In some embodiments, the method is for treating a neurological disease (e.g., a CNS disease), and the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2. In some embodiments, the method is for treating an allergy, and the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigenbinding fragment thereof that specifically binds TNFR1 , CD40, CD27, 4-1 BB, 0X40, GITR, or XEDAR. In some embodiments, the method is for treating a transplant rejection (e.g., an allograft rejection) or a graft-versus-host disease, and the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TNFR1 , 4-1 BB, 0X40, GITR, or XEDAR. In some embodiments, the method is for treating a transplant rejection (e.g., an allograft rejection) or a graft-versus-host disease, and the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds CD30 or TNFR2.

[0431] In some embodiments, the biological fluid is serum or plasma.

[0432] In some embodiments, the reference level of the soluble TNFRSF member protein is the level of the soluble TNFRSF in the biological fluid of a healthy human.

[0433] In some embodiments, the one or more doses of the antibody or antigen-binding fragment thereof is administered to the human subject in one or more treatment periods, in which:

[0434] (a) each dose comprises:

[0435] (i) from about 0.1 mg to about 5000 mg of the antibody or antigen-binding fragment thereof; or

[0436] (ii) from about 0.001 mg / kg to about 50 mg / kg of the antibody or antigen-binding fragment thereof; and / or

[0437] (b) each treatment period lasts one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, or more.

[0438] In some embodiments, the dosing frequency is one or more times a month, every three weeks, every two weeks, a week, every six days, every five days, every four days, every three days, every two days, or a day. In some embodiments, the dosing frequency is once every week (Q1 W), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0439] In some embodiments, the antagonistic or agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein is administered to the human subject subcutaneously.

[0440] In a twenty-fourth aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds human TNFR2, in which the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3, and further in which:

[0441] (a) the CDR-H1 comprises the amino acid sequence of GXTFXXY (SEQ ID NO: 1449), wherein each X is independently a naturally occurring amino acid;

[0442] (b) the CDR-H2 comprises the amino acid sequence of NPNYDS (SEQ ID NO: 1414), NYDSTS (SEQ ID NO: 1420), or a variant thereof with up to two conservative amino acid substitutions;

[0443] (c) the CDR-H3 comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1415) or a variant thereof with up to two conservative amino acid substitutions;

[0444] (d) the CDR-L1 comprises the amino acid sequence of SASSSVRYMY (SEQ ID NO: 1416) or a variant thereof with up to two conservative amino acid substitutions; (e) the CDR-L2 comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1417) or a variant thereof with up to two conservative amino acid substitutions; and

[0445] (f) the CDR-L3 comprises the amino acid sequence of QQWSSNPLT (SEQ ID NO: 1418) or a variant thereof with up to two conservative amino acid substitutions.

[0446] In some embodiments, the CDR-H1 comprises an amino acid sequence selected from the group consisting of GYTFXXY (SEQ ID NO: 1450), GSTFXXY (SEQ ID NO: 1451 ), GTTFXXY (SEQ ID NO: 1452), GCTFXXY (SEQ ID NO: 1453), GNTFXXY (SEQ ID NO: 1454), GQTFXXY (SEQ ID NO: 1455), GXTFSXY (SEQ ID NO: 1456), GXTFCXY (SEQ ID NO: 1457), GXTFYXY (SEQ ID NO: 1458), GXTFNXY (SEQ ID NO: 1459), GXTFQXY (SEQ ID NO: 1460), and GXTFXDY (SEQ ID NO: 1461 ), wherein each X is independently a naturally occurring amino acid

[0447] In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413) or a variant thereof with up to two conservative amino acid substitutions.

[0448] In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413), the CDR-H2 comprises the amino acid sequence of NPNYDS (SEQ ID NO: 1414), the CDR-H3 comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1415), the CDR-L1 comprises the amino acid sequence of SASSSVRYMY (SEQ ID NO: 1416), the CDR-L2 comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1417), and the CDR-L3 comprises the amino acid sequence of QQWSSNPLT (SEQ ID NO: 1418).

[0449] In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413), the CDR-H2 comprises the amino acid sequence of NYDSTS (SEQ ID NO: 1420), the CDR-H3 comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1415), the CDR-L1 comprises the amino acid sequence of SASSSVRYMY (SEQ ID NO: 1416), the CDR-L2 comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1417), and the CDR-L3 comprises the amino acid sequence of QQWSSNPLT (SEQ ID NO: 1418).

[0450] In a twenty-fifth aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds human TNFR2, in which the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3, and further in which:

[0451] (a) the CDR-H1 comprises the amino acid sequence of GYTFTDYNLD (SEQ ID NO: 1425), DYIMH (SEQ ID NO: 1426), or a variant thereof with up to two conservative amino acid substitutions;

[0452] (b) the CDR-H2 comprises the amino acid sequence of DINPNYDS (SEQ ID NO: 1427), WVDPEYGSTDYAEKFKK (SEQ ID NO: 1428), or a variant thereof with up to two conservative amino acid substitutions;

[0453] (c) the CDR-H3 comprises the amino acid sequence of TSYSQKFRG (SEQ ID NO: 1429), DDGSYSPFEDY (SEQ ID NO: 1430), or a variant thereof with up to two conservative amino acid substitutions; (d) the CDR-L1 comprises an amino acid sequence selected from the group consisting of SASSSVRYMYWY (SEQ ID NO: 1431 ), KASENVVTYVS (SEQ ID NO: 1432), RSSQSLVHSNGNTYLH (SEQ ID NO: 1433), KASENVVTYVS (SEQ ID NO: 1434), QASQNINKYIA (SEQ ID NO: 1435), QNINKY (SEQ ID NO: 1436), and a variant thereof with up to two conservative amino acid substitutions;

[0454] (e) the CDR-L2 comprises an amino acid sequence selected from the group consisting of LTSNLAS (SEQ ID NO: 1437), VTSNLAS (SEQ ID NO: 1438), LTSNLGS (SEQ ID NO: 1439), GASNRTY (SEQ ID NO: 1440), IKVSNRFS (SEQ ID NO: 1441 ), DPEYGS (SEQ ID NO: 1442), YTSTLES (SEQ ID NO: 1443), YTS, and a variant thereof with up to two conservative amino acid substitutions; and

[0455] (f) the CDR-L3 comprises an amino acid sequence selected from the group consisting of QQRSNWP (SEQ ID NO: 1445), GQGYSYPYT (SEQ ID NO: 1446), SQTTHVPPT (SEQ ID NO:

[0456] 1447), LQYVNLIT (SEQ ID NO: 1448), and a variant thereof with up to two conservative amino acid substitutions.

[0457] In some embodiments, the CDR-H1 comprises the amino acid sequence of GYTFTDYNLD (SEQ ID NO: 1425) or DYIMH (SEQ ID NO: 1426); the CDR-H2 comprises the amino acid sequence of DINPNYDS (SEQ ID NO: 1427) or WVDPEYGSTDYAEKFKK (SEQ ID NO: 1428); the CDR-H3 comprises the amino acid sequence of TSYSQKFRG (SEQ ID NO: 1429) or DDGSYSPFEDY (SEQ ID NO: 1430); the CDR-L1 comprises an amino acid sequence selected from the group consisting of SASSSVRYMYWY (SEQ ID NO: 1431 ), KASENVVTYVS (SEQ ID NO: 1432), RSSQSLVHSNGNTYLH (SEQ ID NO: 1433), KASENVVTYVS (SEQ ID NO: 1434), QASQNINKYIA (SEQ ID NO: 1435), and QNINKY (SEQ ID NO: 1436); the CDR-L2 comprises an amino acid sequence selected from the group consisting of LTSNLAS (SEQ ID NO: 1437), VTSNLAS (SEQ ID NO: 1438), LTSNLGS (SEQ ID NO: 1439), GASNRTY (SEQ ID NO: 1440), IKVSNRFS (SEQ ID NO: 1441 ), DPEYGS (SEQ ID NO: 1442), YTSTLES (SEQ ID NO: 1443), and YTS; and the CDR-L3 comprises an amino acid sequence selected from the group consisting of QQRSNWP (SEQ ID NO: 1445), GQGYSYPYT (SEQ ID NO: 1446), SQTTHVPPT (SEQ ID NO: 1447), and LQYVNLIT (SEQ ID NO: 1448).

[0458] In a twenty-sixth aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds human TNFR2, in which the antibody or antigen-binding fragment thereof comprises:

[0459] (a) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to any one of SEQ ID NOs: 1486-1490; and

[0460] (b) a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to any one of SEQ ID NOs: 1492-1497.

[0461] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0462] (a) a VH having the amino acid sequence of any one of SEQ ID NOs: 1486-1490; and (b) a VL having the amino acid sequence of any one of SEQ ID NOs: 1492-1497.

[0463] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0464] (a) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1488 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1495;

[0465] (b) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1488 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1497;

[0466] (c) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1489 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1496;

[0467] (d) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1490 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1496; or

[0468] (e) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1490 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1497.

[0469] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0470] (a) a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1495;

[0471] (b) a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1497;

[0472] (c) a VH having the amino acid sequence of SEQ ID NO: 1489 and a VL having the amino acid sequence of SEQ ID NO: 1496;

[0473] (d) a VH having the amino acid sequence of SEQ ID NO: 1490 and a VL having the amino acid sequence of SEQ ID NO: 1496; or

[0474] (e) a VH having the amino acid sequence of SEQ ID NO: 1490 and a VL having the amino acid sequence of SEQ ID NO: 1497.

[0475] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1488 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1495. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1495.

[0476] In some embodiments, the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is a human IgG 1 , human lgG2, human lgG3, or human lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is a human lgG4 antibody or antigen-binding fragment thereof.

[0477] In some embodiments, the antibody or antigen-binding fragment thereof further comprises a human lgG4 Fc domain. In some embodiments, the human lgG4 Fc domain comprises a human lgG4 hinge region having the amino acid substitution S228P numbered according to the EU index (S241 P according to Kabat). In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the amino acid substitution S228P.

[0478] In a twenty-seventh aspect, the disclosure features an antibody or antigen-binding fragment thereof that specifically binds human TNFR2, in which the antibody or antigen-binding fragment thereof comprises:

[0479] (a) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to any one of SEQ ID NOs: 1498-1503; and

[0480] (b) a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to any one of SEQ ID NOs: 1504-1510.

[0481] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0482] (a) a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 1498- 1503; and

[0483] (b) a light chain having the amino acid sequence of any one of SEQ ID NOs: 1504-1510.

[0484] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0485] (a) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1498 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1504;

[0486] (b) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1508;

[0487] (c) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1510;

[0488] (d) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1502 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1509;

[0489] (e) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1503 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1509; or

[0490] (f) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1503 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1510.

[0491] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0492] (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1498 and a light chain having the amino acid sequence of SEQ ID NO: 1504;

[0493] (b) a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1508;

[0494] (c) a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1510;

[0495] (d) a heavy chain having the amino acid sequence of SEQ ID NO: 1502 and a light chain having the amino acid sequence of SEQ ID NO: 1509;

[0496] (e) a heavy chain having the amino acid sequence of SEQ ID NO: 1503 and a light chain having the amino acid sequence of SEQ ID NO: 1509; or

[0497] (f) a heavy chain having the amino acid sequence of SEQ ID NO: 1503 and a light chain having the amino acid sequence of SEQ ID NO: 1510.

[0498] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1508.

[0499] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1508.

[0500] In some embodiments, the antibody or antigen-binding fragment thereof is a human lgG4 antibody or antigen-binding fragment thereof. In some embodiments of the twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh aspect, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds human TNFR2.

[0501] In some embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a singlechain Fv molecule (scFv), a diabody, a triabody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab’)2 molecule, and a tandem scFv (taFv). In some embodiments, the antibody or antigen-binding fragment thereof is a human, humanized, or chimeric antibody or antigen-binding fragment thereof.

[0502] In a twenty-eighth aspect, the disclosure features methods of producing the antibody or antigen-binding fragment thereof disclosed in the twenty-fourth, twenty-fifth, twenty-sixth, or twentyseventh aspect, the methods including expressing a polynucleotide encoding the antibody or antigenbinding fragment thereof in a host cell and recovering the antibody or antigen-binding fragment thereof from host cell medium.

[0503] In a twenty-ninth aspect, the disclosure features constructs comprising a first polypeptide domain and a second polypeptide domain, in which the first polypeptide domain and the second polypeptide domain are each, independently, an antigen-binding fragment disclosed in the twentyfourth, twenty-fifth, twenty-sixth, or twenty-seventh aspect of the disclosure.

[0504] In some embodiments, the first polypeptide domain and the second polypeptide domain are bound by a covalent linker. In some embodiments, the covalent linker comprises an amide bond or a disulfide bond.

[0505] In a thirtieth aspect, the disclosure features polynucleotides encoding the antibody or antigenbinding fragment thereof disclosed in the twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh aspect of the disclosure or the construct disclosed in the twenty-seventh aspect of the disclosure.

[0506] In a thirty-first aspect, the disclosure features vectors comprising the polynucleotide disclosed in the thirtieth aspect of the disclosure.

[0507] In some embodiments, the vector is an expression vector. In some embodiments, the expression vector is a eukaryotic expression vector.

[0508] In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is selected from the group consisting of an adenovirus, retrovirus, poxvirus, adeno-associated virus, baculovirus, herpes simplex virus, and vaccinia virus. In some embodiments, the adenovirus is a serotype 1 -60 adenovirus. In some embodiments, the adenovirus is a serotype 5, 26, 35, or 48 adenovirus. In some embodiments, the retrovirus is a y-retrovirus or a lentivirus. In some embodiments, the vaccinia virus is a modified vaccinia Ankara (MVA).

[0509] In a thirty-second aspect, the disclosure features isolated host cells comprising the vector disclosed in the thirty-first aspect of the disclosure.

[0510] In some embodiments, the host cell is a prokaryotic cell or a eukaryotic cell. In some embodiments, the eukaryotic cell is a mammalian cell. In some embodiments, the mammalian cell is a CHO cell.

[0511] In a thirty-third aspect, the disclosure features pharmaceutical compositions comprising the antibody or antigen-binding fragment thereof disclosed in the twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh aspect of the disclosure, the construct disclosed in the twenty-ninth aspect of the disclosure, the polynucleotide disclosed in the thirtieth aspect of the disclosure, the vector disclosed in the thirty-first aspect of the disclosure, or the host cell disclosed in the thirty-second aspect of the disclosure, and a pharmaceutically acceptable carrier or excipient.

[0512] In a thirty-fourth aspect, the disclosure features methods of modulating an immune response in a human subject, the method comprising administering to the subject the antibody or antigenbinding fragment thereof disclosed in the twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh aspect of the disclosure, the construct disclosed in the twenty-ninth aspect of the disclosure, the polynucleotide disclosed in the thirtieth aspect of the disclosure, the vector disclosed in the thirty-first aspect of the disclosure, the host cell disclosed in the thirty-second aspect of the disclosure, or the pharmaceutical composition disclosed in the thirty-third aspect of the disclosure.

[0513] In some embodiments, the method is for treating a cell proliferation disorder, an autoimmune disease, an infectious disease, an inflammatory disease, a neurological disease, an allergy, a transplant rejection (e.g., an allograft rejection), or a graft-versus-host disease in the human subject. In some embodiments, the method is for transplantation or for regenerating a tissue or organ in the human subject.

[0514] In some embodiments, the method is for treating a cancer. In some embodiments, the human subject has a blood (e.g., serum or plasma) level of soluble TNFR2 that is normal or lower than a reference level of soluble TNFR2. In some embodiments, the method is for increasing the serum or plasma level of soluble TNFR2 in the human subject

[0515] In some embodiments, the method further comprises:

[0516] (a) obtaining a biological fluid (e.g., blood, plasma, or serum) from the human subject;

[0517] (b) detecting a decreased (e.g., by 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) level of soluble TNFR2 in the biological fluid of the subject relative to a reference level of soluble TNFR2; and

[0518] (c) administering to the subject one or more doses of the antibody or antigen-binding fragment thereof at a dosing frequency. In some embodiments, the method further comprises:

[0519] (a) detecting a normal or decreased (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) level of soluble TNFR2 in the subject relative to a reference level of soluble TNFR2, and increasing the level of soluble TNFR2 by administering an increased dosage and / or dosing frequency of the antibody or antigen-binding fragment thereof to increase the level of soluble TNFR2; or

[0520] (b) detecting an increased (e.g., by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more) level of soluble TNFR2 in the subject relative to a reference level of soluble TNFR2, and increasing the dosage and / or dosing frequency of the antibody or antigen-binding fragment thereof.

[0521] In some embodiments, the antibody or antigen-binding fragment thereof is administered to the human subject at a dosing frequency of once every week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the antibody or antigen-binding fragment thereof is administered to the human subject at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg (e.g., about 0.8 mg / kg, about 0.85 mg / kg, about 0.9 mg / kg, about 0.95 mg / kg, about 1 .0 mg / kg, about 1 .05 mg / kg, about 1 .1 mg / kg, about 1.15 mg / kg, or about 1 .2 mg / kg), from about 1 .65 mg / kg to about 2.5 mg / kg (e.g., about 1 .65 mg / kg, about 1 .7 mg / kg, about 1 .75 mg / kg, about 1 .8 mg / kg, about 1 .85 mg / kg, about 1 .9 mg / kg, about 1 .95 mg / kg, about 2.0 mg / kg, about 2.05 mg / kg, about 2.1 mg / kg, about 2.15 mg / kg, about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, or about 2.5 mg / kg), from about 2.2 mg / kg to about 3.0 mg / kg (e.g., about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, about 2.5 mg / kg, about 2.55 mg / kg, about 2.6 mg / kg, about 2.65 mg / kg, about 2.7 mg / kg, about 2.75 mg / kg, about 2.8 mg / kg, about 2.85 mg / kg, about 2.9 mg / kg, about 2.95 mg / kg, or about 3.0 mg / kg), or from about 2.5 mg / kg to about 4.2 mg / kg (e.g., about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, or about 4.2 mg / kg). In some embodiments, the antibody or antigen-binding fragment thereof is administered to the human subject:

[0522] (a) once every week at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg (e.g., about 0.8 mg / kg, about 0.85 mg / kg, about 0.9 mg / kg, about 0.95 mg / kg, about 1 .0 mg / kg, about 1 .05 mg / kg, about 1 .1 mg / kg, about 1.15 mg / kg, or about 1 .2 mg / kg);

[0523] (b) once every two weeks at a dose of from about 1 .65 mg / kg to about 2.5 mg / kg (e.g., about 1 .65 mg / kg, about 1 .7 mg / kg, about 1 .75 mg / kg, about 1 .8 mg / kg, about 1 .85 mg / kg, about 1 .9 mg / kg, about 1 .95 mg / kg, about 2.0 mg / kg, about 2.05 mg / kg, about 2.1 mg / kg, about 2.15 mg / kg, about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, or about 2.5 mg / kg); (c) once every three weeks at a dose of from about 2.2 mg / kg to about 3.0 mg / kg (e.g., about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, about 2.5 mg / kg, about 2.55 mg / kg, about 2.6 mg / kg, about 2.65 mg / kg, about 2.7 mg / kg, about 2.75 mg / kg, about 2.8 mg / kg, about 2.85 mg / kg, about 2.9 mg / kg, about 2.95 mg / kg, or about 3.0 mg / kg); or

[0524] (d) once every four weeks at a dose of from about 2.5 mg / kg to about 4.2 mg / kg (e.g., about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, or about 4.2 mg / kg).

[0525] In some embodiments, the method further comprises decreasing the dose range of the antibody or antigen-binding fragment thereof.

[0526] Definitions

[0527] As used herein, the term “about” refers to a value that is no more than 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 nM to 5.5 nM.

[0528] As used herein, the term “antibody” (Ab) refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen, and includes polyclonal, monoclonal, genetically engineered and otherwise modified forms of antibodies, including but not limited to chimeric antibodies, humanized antibodies, primatized antibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies), and antigen-binding fragments of antibodies, including e.g., Fab’, F(ab’)2, Fab, Fv, IgG, and scFv fragments. Moreover, unless otherwise indicated, the term “monoclonal antibody” (mAb) is meant to include both intact molecules, as well as antibody fragments (such as, for example, Fab and F(ab’)2 fragments) that are capable of specifically binding to a target protein.

[0529] The term “antigen-binding fragment,” as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to a target antigen. The antigen-binding function of an antibody can be performed by fragments of a full-length antibody. The antibody fragments can be a Fab, F(ab’)2, scFv, SMIP, diabody, a triabody, an affibody, a nanobody, an aptamer, or a domain antibody. Examples of binding fragments encompassed of the term “antigen-binding fragment” of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab’)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb including VH and VL domains; (vi) a dAb fragment (Ward et al., Nature 341 :544-546, 1989), which consists of a VH domain; (vii) a dAb which consists of a VH or a VL domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., Science 242:423-426, 1988, and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988). These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies. An “antigen-binding fragment” may also refer to a linear or non-linear peptide, which may be cyclic, bicylic, and / or conformationally biased. It will be appreciated by one of skill in the art that a conformationally biased antigen-binding fragment will entail a structure-based design such that the peptide includes an antigen-binding site mimic based on the 3D structure of the peptide-antigen complex. Such structural information enables the design and generation of mimics of continuous, as well as of sequentially discontinuous antigen-binding sites, which are composed of two or more protein segments that are distant in protein sequence but brought into spatial proximity through protein folding. Mimicking such discontinuous antigen-binding sites by synthetic peptides often involves splicing and / or molecular scaffolds (e.g., disulfide bonds) to enable conformation bias. See e.g., Gro3 et al., Front. Bioeng. Biotechnol. 4(39), 2016. Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in some embodiments, by chemical peptide synthesis procedures known in the art.

[0530] As used herein, the terms “agonistic TNFRSF antibody,” “agonistic anti-TNFRSF antibody,” and “TNFRSF agonist antibody” refer to TNFRSF antibodies that are capable of inducing or promoting the activation of a TNFRSF member protein (e.g., TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL- R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, or DCR3), augmenting one or more signal transduction pathways mediated by the TNFRSF member protein, and / or inducing or promoting at least one activity mediated by the activation of the TNFRSF member protein. For example, agonistic TNFRSF antibodies may induce or promote the growth and proliferation of T-reg cells. Agonistic TNFRSF antibodies may induce or promote TNFRSF activation by allosterically binding TNFRSF. In this way, agonistic TNFRSF antibodies may promote or stabilize the trimerization of the TNFRSF member protein that is induced by interacting with one or more ligands in the TNF superfamily (e.g., CD40L for CD40, TNFa for TNFR1 and TNFR2, 4-1 BBL for 4- 1 BB, CD70 for CD27, CD153 for CD30, N-APP for DR6, EDA-A1 for EDAR, FasL for Fas, GITRL for GITR, LTa for HVEM, LT-p (TNF-C) for LT-p receptor complex, NGF for NGFR, TRAIL for OPG, OX40L for 0X40, RANKL for RANK, TRAIL for TRAIL-R2 (TNFRSF1 OB), TRAIL-R1 (TNFRSF1 OA), and TRAIL-R4, TL1 A for TRAMP, EDA-A2 for XEDAR, or FasL, LIGHT, and TL1 A for DCR3, among others), thus resulting in induction of the TNFRSF member protein activity. As used herein, the terms “antagonistic TNFRSF antibody,” “antagonistic anti-TNFRSF antibody,” and “TNFRSF antagonist antibody” refer to TNFRSF antibodies that are capable of inhibiting or reducing the activation of a TNFRSF member protein (e.g., TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, or DCR3), attenuating one or more signal transduction pathways mediated by the TNFRSF member protein, and / or reducing or inhibiting at least one activity mediated by the activation of the TNFRSF member protein. For example, antagonistic TNFRSF antibodies may inhibit or reduce the growth and proliferation of T-reg cells. Antagonistic TNFRSF antibodies may inhibit or reduce TNFRSF activation by blocking TNFRSF from binding one or more ligands in the TNF superfamily, e.g., CD40L for CD40, TNFa for TNFR1 and TNFR2, 4-1 BBL for 4-1 BB, CD70 for CD27, CD153 for CD30, N-APP for DR6, EDA-A1 for EDAR, FasL for Fas, GITRL for GITR, LTa for HVEM, LT-p (TNF- C) for LT-p receptor complex, NGF for NGFR, TRAIL for OPG, OX40L for 0X40, RANKL for RANK, TRAIL for TRAIL-R2 (TNFRSF1 OB), TRAIL-R1 (TNFRSF1 OA), and TRAIL-R4, TL1 A for TRAMP, EDA-A2 for XEDAR, or FasL, LIGHT, and TL1 A for DCR3, among others. In this way, antagonistic TNFRSF antibodies may block the trimerization of the TNFRSF member protein that would otherwise be induced by interacting with one or more ligands in the TNF superfamily (e.g., CD40L, TNFa, 4- 1 BBL, CD70, CD153, or RANKL, among others), thus resulting in suppression of the TNFRSF member protein activity.

[0531] As used herein, the term “bispecific antibody” refers to an antibody (e.g., a monoclonal, often a human or humanized, antibody) that has binding specificities for at least two different antigens. For example, one of the binding specificities can be directed towards a TNFRSF member protein (e.g., TNFR2, TNFR1 , CD40, 4-1 BB, CD27, CD30, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R2 (TNFRSF10B), TRAIL-R1 (TNFRSF10A), TRAIL-R4, TRAMP, TROY, XEDAR, or DCR3), and the other can be for any other antigen, e.g., for a cell-surface protein, receptor, receptor subunit, tissue-specific antigen, virally derived protein, virally encoded envelope protein, bacterial ly derived protein, or bacterial surface protein, etc.

[0532] As used herein, the term “chimeric antibody” refers to an antibody having variable domain sequences (e.g., CDR sequences) derived from an immunoglobulin of one source organism, such as rat or mouse, and constant regions derived from an immunoglobulin of a different organism (e.g., a human, a non-human primate, pig, goat, rabbit, hamster, cat, dog, guinea pig, a member of the Bo vidae family (such as cattle, cow, bison, buffalo, elk, and yaks, among others), sheep, or horse, among others). Methods for producing chimeric antibodies are known in the art. See, e.g., Morrison, Science 229:1202-7, 1985; Oi et al., BioTechniques 4:214-221 , 1986; Gillies et al., J. Immunol. Methods 125:191 -202, 1985; U.S. Pat. Nos. 5,807,715; 4,816,567; and 4,816,397; incorporated herein by reference. As used herein, the term “diabodies” refers to bivalent antibodies comprising two polypeptide chains, in which each polypeptide chain includes VH and VL domains joined by a linker that is too short (e.g., a linker composed of five amino acids) to allow for intramolecular association of VH and VL domains on the same peptide chain. This configuration forces each domain to pair with a complementary domain on another polypeptide chain to form a homodimeric structure. Accordingly, the term “triabodies” refers to trivalent antibodies comprising three peptide chains, each of which contains one VH domain and one VL domain joined by a linker that is exceedingly short (e.g., a linker composed of 1 -2 amino acids) to permit intramolecular association of VH and VL domains within the same peptide chain. In order to fold into their native structure, peptides configured in this way typically trimerize to position the VH and VL domains of neighboring peptide chains spatially proximal to one another to permit proper folding (see Holliger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993; incorporated herein by reference).

[0533] As used herein, the term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.

[0534] As used herein, the term “multispecific antibodies” refers to antibodies that exhibit affinity for more than one target antigen. Multispecific antibodies can have structures similar to full immunoglobulin molecules and include Fc regions, for example, IgG Fc regions. Such structures can include, but are not limited to, IgG-Fv, lgG-(scFv)2, DVD-lg, (scFv)2-(scFv)2-Fc, and (scFv)2-Fc- (SCFV)2. In case of lgG-(scFv)2, the scFv can be attached to either the N-terminal or the C- terminal end of either the heavy chain or the light chain. Exemplary multi-specific molecules that include Fc regions and into which anti-TNFRSF antibodies or antigen-binding fragments thereof can be incorporated have been reviewed by Kontermann, mAbs 4:182-197, 2012; Yazaki et al., Protein Engineering, Design & Selection 26:187-193, 2013; and Grote et al., 2012, in Proetzel & Ebersbach (eds.), Antibody Methods and Protocols, Methods in Molecular Biology vol. 901 , chapter 16:247-263; incorporated herein by reference. In some embodiments, antibody fragments can be components of multi-specific molecules without Fc regions, based on fragments of IgG or DVD or scFv. Exemplary multi-specific molecules that lack Fc regions and into which antibodies or antibody fragments can be incorporated include scFv dimers (diabodies), trimers (triabodies) and tetramers (tetrabodies), Fab dimers (conjugates by adhesive polypeptide or protein domains) and Fab trimers (chemically conjugated), are described by Hudson and Souriau, Nature Medicine 9:129-134, 2003; incorporated herein by reference.

[0535] As used herein, the term “human antibody” refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, CL, CH domains (e.g., CH1 , CH2, CH3), hinge, VL, and VH) is substantially non-immunogenic in humans, with only minor sequence changes or variations. A human antibody can be produced in a human cell (e.g., by recombinant expression), or by a non-human animal or a prokaryotic or eukaryotic cell that can express functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. Further, when a human antibody is a single-chain antibody, it can include a linker peptide that is not found in native human antibodies. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered of human origin. Human antibodies can be made by a variety of methods known in the art including phage display methods using antibody libraries derived from human immunoglobulin sequences. See U.S. Patent Nos. 4,444,887 and 4,716,111 ; and PCT publications WO 1998 / 46645; WO 1998 / 50433; WO 1998 / 24893; WO 1998 / 16654; WO 1996 / 34096; WO 1996 / 33735; and WO 1991 / 10741 ; incorporated herein by reference. Human antibodies can also be produced using transgenic mice that are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. See, e.g., PCT publications WO 98 / 24893; WO 92 / 01047; WO 96 / 34096; WO 96 / 33735; U.S. Patent Nos. 5,413,923; 5,625, 126; 5,633,425; 5,569,825; 5,661 ,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771 ; and 5,939,598; incorporated by reference herein.

[0536] As used herein, the term “humanized” antibody refers to forms of non-human (e.g., murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab’, F(ab’)2 or other target-binding subdomains of antibodies) which contain minimal sequences derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin. All, or substantially all, of the FR regions may also be those of a human immunoglobulin sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence. Methods of antibody humanization are known in the art. See, e.g., Riechmann et al., Nature 332:323-7, 1988; U.S. Patent Nos 5,225,539; 5,530,101 ; 5,585,089; 5,693,761 ; 5,693,762; and 6,180,370; EP239400; PCT publication WO 91 / 09967; EP592106; and EP519596; incorporated herein by reference.

[0537] As used herein, the term “primatized antibody” refers to an antibody comprising framework regions from primate-derived antibodies and other regions, such as CDRs and / or constant regions, from antibodies of a non-primate source. Methods for producing primatized antibodies are known in the art. See, e.g., U.S. Patent Nos. 5,658,570; 5,681 ,722; and 5,693,780; incorporated herein by reference. For instance, a primatized antibody or antigen-binding fragment thereof described herein can be produced by inserting the CDRs of a non-primate antibody or antigen-binding fragment thereof into an antibody or antigen-binding fragment thereof that contains one or more framework regions of a primate.

[0538] As used herein, the term “scFv” refers to a single-chain Fv antibody in which the variable domains of the heavy chain and the light chain from an antibody have been joined to form one chain. scFv fragments contain a single polypeptide chain that includes the variable region of an antibody light chain (VL) (e.g., CDR-L1 , CDR-L2, and / or CDR-L3) and the variable region of an antibody heavy chain (VH) (e.g., CDR-H1 , CDR-H2, and / or CDR-H3) separated by a linker. The linker that joins the VL and VH regions of a scFv fragment can be a peptide linker composed of proteinogenic amino acids. Alternative linkers can be used to so as to increase the resistance of the scFv fragment to proteolytic degradation (e.g., linkers containing D-amino acids), to enhance the solubility of the scFv fragment (e.g., hydrophilic linkers, such as polyethylene glycol-containing linkers or polypeptides containing repeating glycine and serine residues), to improve the biophysical stability of the molecule (e.g., a linker containing cysteine residues that form intramolecular or intermolecular disulfide bonds), or to attenuate the immunogenicity of the scFv fragment (e.g., linkers containing glycosylation sites). scFv molecules are known in the art and are described, e.g., in U.S. Patent No. 5,892,019; Flo et al., Gene 77:51 , 1989; Bird et al., Science 242:423, 1988; Pantoliano et al., Biochemistry 30:10117, 1991 ; Milenic et al., Cancer Research 51 :6363, 1991 ; and Takkinen et al., Protein Engineering 4:837, 1991 . The VL and VH domains of a scFv molecule can be derived from one or more antibody molecules. It is also understood by one of ordinary skill in the art that the variable regions of the scFv molecules described herein can be modified, such that they vary in amino acid sequence from the antibody molecule from which they were derived. For example, in some embodiments, nucleotide or amino acid substitutions leading to conservative substitutions or changes at amino acid residues can be made (e.g., in CDR and / or framework residues). Alternatively or in addition, mutations are made to CDR amino acid residues to optimize antigen binding using art recognized techniques. scFv fragments are described, for example, in WO 2011 / 084714; incorporated herein by reference.

[0539] As used herein, a “disulfide-bonded isoform” of an antibody or antigen-binding fragment thereof is a form of the antibody or antigen-binding fragment thereof having a particular internal disulfide bonding pattern. Disulfide-bonded isoforms are structural isomers of a given antibody or antigen-binding fragment thereof that do not differ from one another in amino acid sequence but exhibit different disulfide bond connectivity. For example, in the context of a human lgG2 antibody or variant thereof, the antibody may exist in one of four possible disulfide-bonded isoforms, represented herein as isoforms lgG2-A, lgG2-B, lgG2-A / Bi, and lgG2-A / B2.

[0540] As used herein, the term “complementarity determining region” (CDR) refers to a hypervariable region found both in the light chain and the heavy chain variable domains of an antibody. The more highly conserved portions of variable domains are called the framework regions (FRs). As is appreciated in the art, the amino acid positions that delineate a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art. Some positions within a variable domain may be viewed as hybrid hypervariable positions in that these positions can be deemed to be within a hypervariable region under one set of criteria while being deemed to be outside a hypervariable region under a different set of criteria. One or more of these positions can also be found in extended hypervariable regions. The antibodies described herein may comprise modifications in these hybrid hypervariable positions. The variable domains of native heavy and light chains each comprise four framework regions that primarily adopt a p-sheet configuration, connected by three CDRs, which form loops that connect, and in some cases form part of, the p-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions in the order FR1 -CDR1 -FR2-CDR2-FR3-CDR3-FR4 and, with the CDRs from the other antibody chains, contribute to the formation of the target binding site of antibodies (see Kabat et al, Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md. 1987); incorporated herein by reference). As used herein, numbering of immunoglobulin amino acid residues is done according to the EU numbering system (see, e.g., Edelman et al. Proc. Natl. Acad. Sci. USA 63:78- 85, 1969; incorporated herein by reference), unless otherwise indicated. The CDRs can be identified using sequence or structure-based methods that have been described by Kabat et al., Chothia et al. (J. Mol. Biol. 196:901 -917, 1987), and MacCallum et al. (J. Mol. Biol. 262:732-745, 1996), where the definitions include overlapping or subsets of amino acid residues when compared against each other. The term “CDR” may be, for example, a CDR as defined by Kabat or Chothia based on sequence comparisons.

[0541] As used herein, the term “framework region” or “FW region” includes amino acid residues that are adjacent to the CDRs. FW region residues may be present in, for example, human antibodies, rodent-derived antibodies (e.g., murine antibodies), humanized antibodies, primatized antibodies, chimeric antibodies, antibody fragments (e.g., Fab fragments), single-chain antibody fragments (e.g., scFv fragments), antibody domains, and bispecific antibodies, among others.

[0542] As used herein, the terms “conservative mutation,” “conservative substitution,” or “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 / or steric volume. These properties are summarized for each of the twenty naturally occurring amino acids in Table 1 below.

[0543] Table 1. Representative physicochemical properties of naturally occurring amino acids.

[0544] From this table, it is appreciated that the conservative amino acid families include, but are not limited to: (i) G, A, V, L, I, P, and M; (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). As is appreciated in the art, a polypeptide may retain its biological properties or functions after the introduction of one or more conservative substitutions.

[0545] Amino acid substitutions may be represented herein using the convention (AA1 )(N)(AA2), where “AA1 ” represents the amino acid normally present at particular site within an amino acid sequence, “N” represents the residue number within the amino acid sequence at which the substitution occurs, and “AA2” represents the amino acid present in the amino acid sequence after the substitution is effectuated. For example, the notation “C232S” in the context of an antibody hinge region, such as an lgG2 antibody hinge region, refers to a substitution of the naturally occurring cysteine residue for a serine residue at amino acid residue 232 of the indicated hinge amino acid sequence. Likewise, the notation “C233S” in the context of an antibody hinge region, such as an lgG2 antibody hinge region, refers to a substitution of the naturally occurring cysteine residue for a serine residue at amino acid residue 233 of the indicated hinge amino acid sequence.

[0546] As used herein, the term “hydrophobic side chain” refers to an amino acid side chain that exhibits relatively low solubility in water due to, e.g., the steric or electronic properties of the chemical moieties present within the side chain. Examples of amino acids containing hydrophobic side chains include those containing aliphatic hydrocarbons, such as alanine, valine, leucine, isoleucine, proline, and methionine, as well as amino acids containing aromatic ring systems that are electrostatically neutral at physiological pH, such as tryptophan, phenylalanine, and tyrosine.

[0547] As used herein, the term “conjugate” refers to a compound formed by the chemical bonding of a reactive functional group of one molecule with an appropriately reactive functional group of another molecule.

[0548] As used herein, the term “chemotherapeutic agent” refers to any chemical agent with therapeutic usefulness in the treatment of cancer, such as a cancer described herein. Chemotherapeutic agents encompass both chemical and biological agents. These agents can function to inhibit a cellular activity upon which a cancer cell depends for continued survival. Categories of chemotherapeutic agents include alkylating / alkaloid agents, antimetabolites, hormones, hormone analogs, and antineoplastic drugs. Exemplary chemotherapeutic agents suitable for use in conjunction with the compositions and methods described herein include, without limitation, those set forth in Slapak and Kufe, Principles of Cancer Therapy, Chapter 86 in Harrison’s Principles of Internal medicine, 14thedition; Perry et al., Chemotherapeutic, Chapter 17 in Abeloff, Clinical Oncology 2nded., 2000; Baltzer L. and Berkery R. (eds): Oncology Pocket Guide to Chemotherapeutic, 2nded. St. Louis, Mosby-Year Book, 1995; Fischer D. S., Knobf M. F., Durivage H.J. (eds): The Cancer Chemotherapeutic Handbook, 4thed. St. Louis, Mosby-Year Handbook, the disclosures of each of which are incorporated herein by reference as they pertain to chemotherapeutic agents.

[0549] As used herein, the term “immunotherapy agent” refers to a compound, such as an antibody, antigen-binding fragment thereof, single-chain polypeptide, or construct as described herein, that specifically binds an immune checkpoint protein (e.g., immune checkpoint receptor or ligand) and exerts an antagonistic effect on the receptor or ligand, thereby reducing or inhibiting the signal transduction of the receptor or ligand that would otherwise lead to a downregulation of the immune response. Immunotherapy agents include compounds, such as antibodies, antigen-binding fragments, single-chain polypeptides, and constructs, capable of specifically binding receptors expressed on the surfaces of hematopoietic cells, such as lymphocytes (e.g., T cells), and suppressing the signaling induced by the receptor or ligand that would otherwise lead to tolerance towards an endogenous (“self”) antigen, such as a tumor-associated antigen. Immunotherapy agents may reduce the signaling induced by the receptor or ligand by, for example, 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% relative to the signaling induced by the receptor or ligand exhibited in the absence of the immunotherapy agent. Exemplary assays that can be used to measure the extent of receptor or ligand signaling include, for example, enzyme-linked immunosorbent assay (ELISA) techniques to measure protein expression alterations that are associated with a particular signal transduction pathway, as well as polymerase chain reaction (PCR)-based techniques, such as quantitative PCR, reverse-transcription PCR, and real-time PCR experiments useful for determining changes in gene expression associated with a particular signal transduction pathway, among others. Exemplary methods that can be used to determine whether an agent is an “immunotherapy agent” include the assays described in Mahoney et al., Cancer Immunotherapy 14:561 -584, 2015, the disclosure of which is incorporated herein by reference in its entirety. Examples of immunotherapy agents include, e.g., antibodies or antigen-binding fragments thereof that specifically bind one or more of TL1 A, CD40L, LIGHT, BTLA, LAG3, TIM3, Singlecs, ICOS, B7-H3, B7-H4, VISTA, TMIGD2, BTNL2, CD48, KIR, LIR, LIR antibody, ILT, NKG2D, NKG2A, MICA, MICB, CD244, CSF1 R, IDO, TGFp, CD39, CD73, CXCR4, CXCL12, SIRPA, CD47, VEGF, and neuropilin. Additional examples of immunotherapy agents include Targretin, Interferon-alpha, clobetasol, Peg Interferon (e.g., PEGASYS®), prednisone, Romidepsin, Bexarotene, methotrexate, Triamcinolone cream, anti- chemokines, Vorinostat, gabapentin, antibodies to lymphoid cell surface receptors and / or lymphokines, antibodies to surface cancer proteins, and / or small molecular therapies such as Vorinostat. Particular examples of immunotherapy agents that may be used in or in conjunction with the compositions and methods described herein include anti-PD-1 antibodies and antigen-binding fragments thereof, such as nivolumab, pembrolizumab, avelumab, durvalumab, and atezolizumab, as well as anti-PD-L1 antibodies and antigen-binding fragments thereof, such as atezolizumab and avelumab, and anti-CTLA-4 antibodies and antigen-binding fragments thereof, such as ipilimumab or tremelimumab.

[0550] As used herein in the context of a TNFRSF agonist or antagonist, the term “construct” refers to a fusion protein containing a first polypeptide domain bound to a second polypeptide domain. The polypeptide domains may each independently be agonistic or antagonistic antigen-binding fragments that bind TNFRSF member proteins (e.g., single chain polypeptides as described herein). The first polypeptide domain may be covalently bound to the second polypeptide domain, for instance, by way of a linker, such as a peptide linker or a disulfide bridge, among others. Exemplary linkers that may be used to join the polypeptide domains of a TNFRSF agonist or antagonist construct include, without limitation, those that are described in Leriche et al., Bioorg. Med. Chem. 20:571 -582, 2012, the disclosure of which is incorporated herein by reference in its entirety.

[0551] As used herein, the term “endogenous” describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that is found naturally in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, tissue, or cell, such as a human cell).

[0552] As used herein, the term “exogenous” describes a molecule (e.g., a polypeptide, nucleic acid, or cofactor) that is not found naturally in a particular organism (e.g., a human) or in a particular location within an organism (e.g., an organ, a tissue, or a cell, such as a human cell). Exogenous materials include those that are provided from an external source to an organism or cultured matter.

[0553] As used herein, the term “epitope” refers to a portion of an antigen that is recognized and bound by a polypeptide, such as an antibody, antigen-binding fragment thereof, single-chain polypeptide, or construct as described herein. In the context of a protein antigen (such as a human TNFRSF member protein), an epitope may be a continuous epitope, which is a single, uninterrupted segment of one or more amino acids covalently linked to one another by peptide bonds in which all of the component amino acids bind the polypeptide (e.g., antibody, antigen-binding fragment thereof, single-chain polypeptide, or construct thereof). Continuous epitopes may be composed, for instance, of 1 , 5, 10, 15, 20, or more amino acids within an antigen, such as a human TNFRSF member protein. In some embodiments, an epitope may be a discontinuous epitope, which contains two or more amino acids each separated from one another in the amino acid sequence of an antigen by one or more intervening amino acid residues. Despite this separation by intervening amino acids, the segments that compose a discontinuous epitope may be, for instance, spatially proximal to one another in the three-dimensional conformation of the antigen.

[0554] As used herein, the term “fusion protein” refers to a protein that is joined via a covalent bond to another molecule. A fusion protein can be chemically synthesized by, e.g., an amide-bond forming reaction between the N-terminus of one protein to the C-terminus of another protein. Alternatively, a fusion protein containing one protein covalently bound to another protein can be expressed recombinantly in a cell (e.g., a eukaryotic cell or prokaryotic cell) by expression of a polynucleotide encoding the fusion protein, for example, from a vector or the genome of the cell. A fusion protein may contain one protein that is covalently bound to a linker, which in turn is covalently bound to another molecule. Examples of linkers that can be used for the formation of a fusion protein include peptide-containing linkers, such as those that contain naturally occurring or non-naturally occurring amino acids. In some embodiments, it may be desirable to include D-amino acids in the linker, as these residues are not present in naturally occurring proteins and are thus more resistant to degradation by endogenous proteases. Linkers can be prepared using a variety of strategies that are well known in the art, and depending on the reactive components of the linker, can be cleaved by enzymatic hydrolysis, photolysis, hydrolysis under acidic conditions, hydrolysis under basic conditions, oxidation, disulfide reduction, nucleophilic cleavage, or organometallic cleavage (Leriche et al., Bioorg. Med. Chem. 20:571 -582, 2012).

[0555] As used herein, the term “hinge region” refers to the domain of an antibody or antigen-binding fragment thereof (e.g., an lgG2 antibody or antigen-binding fragment thereof) located between the antigen-binding portion(s) of the antibody or antigen-binding fragment thereof, such as the Fab region of the antibody or antigen-binding fragment thereof, and the portion of the antibody or antigen-binding fragment thereof that dictates the isotype of the antibody or antigen-binding fragment thereof, such as the Fc region of the antibody or antigen-binding fragment thereof. For example, in the context of a monoclonal antibody, the hinge region is the polypeptide situated approximately in the center of each heavy chain, connecting the CH1 domain to the CH2 and CH3 domains. The hinge region of an antibody or antigen-binding fragment thereof may provide a chemical linkage between chains of the antibody or antigen-binding fragment thereof. For instance, in a monoclonal antibody, the cysteine residues within the hinge region form inter-chain disulfide bonds, thereby providing explicit covalent bonds between heavy chains. The amino acid sequence of wild-type human lgG2 is ERKCCVECPPCP (SEQ ID NO: 51 ). As used herein, antibody hinge regions are numbered according to the numbering system of Kabat et al, Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md. 1987), the disclosure of which is incorporated herein by reference.

[0556] As used herein, the term “myeloid-derived suppressor cell” or “MDSC” refers to a cell of the immune system that modulates the activity of a variety of effector cells and antigen-presenting cells, such as T cells, NK cells, dendritic cells, and macrophages, among others. Myeloid derived suppressor cells are distinguished by their gene expression profile, and express all or a subset of proteins and small molecules selected from the group consisting of B7-1 (CD80), B7-H1 (PD-L1 ), CCR2, CD1 d, CD1 d1 , CD2, CD31 (PECAM-1 ), CD43, CD44, complement component C5a R1 , F4 / 80 (EMR1 ), Fey Rill (CD16), Fey RII (CD32), Fey RIIA (CD32a), Fey RUB (CD32b), Fey RIIB / C (CD32b / c), Fey RIIC (CD32c), Fey RIIIA (CD16A), Fey RIIIB (CD16b), galectin-3, GP130, Gr-1 (Ly- 6G), ICAM-1 (CD54), IL-1 Rl, IL-4Ra, IL-6Ra, integrin a4 (CD49d), integrin aL (CD1 1 a), integrin aM (CD1 1 b), M-CSFR, MGL1 (CD301 a), MGL1 / 2 (CD301 a / b), MGL2 (CD301 b), nitric oxide, PSGL-1 (CD162), L-selectin (CD62L), siglec-3 (CD33), transferrin receptor (TfR), VEGFR1 (Flt-1 ), and VEGFR2 (KDR or Flk-1 ). Particularly, MDSCs do not express proteins selected from the group consisting of B7-2 (CD86), B7-H4, CD1 1 c, CD14, CD21 , CD23 (FCERII), CD34, CD35, CD40 (TNFRSF5), CD1 17 (c-kit), HLA-DR, and Sca-1 (Ly6).

[0557] As used herein, the term “percent (%) sequence identity” refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence that are identical to the amino acid (or nucleic acid) residues of a reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity (e.g., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software, such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, a reference sequence aligned for comparison with a candidate sequence may show that the candidate sequence exhibits from 50% to 100% sequence identity across the full length of the candidate sequence or a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence. The length of the candidate sequence aligned for comparison purposes may be, for example, at least 30%, (e.g., 30%, 40, 50%, 60%, 70%, 80%, 90%, or 100%) of the length of the reference sequence. When a position in the candidate sequence is occupied by the same amino acid residue as the corresponding position in the reference sequence, the molecules are identical at that position.

[0558] As used herein, the term “proliferation” in the context of a population of cells, such as a population of TNFRSF-expressing cells (e.g., T-reg cells, MDSCs, or TNFRSF-expressing cancer cells) refers to mitotic and cytokinetic division of a cell to produce a plurality of cells. Cell proliferation may be evidenced, for example, by a finding that the quantity of cells (e.g., TNFRSF-expressing cells) in a subject or sample of cells has increased over a given time period, such as over the course of one or more hours, days, or weeks. One of skill in the art may monitor cell proliferation using a variety of known techniques, such as by way of visual microscopy, hemocytometry, flow cytometry, fluorescence activated cell sorting, and other assays known in the art. In the present disclosure, cell proliferation is considered changed (e.g., increased or decreased) when the rate of proliferation of a population of cells, such as a population of TNFRSF-expressing cells contacted with an agonistic or antagonistic TNFRSF antibody or antigen-binding fragment thereof described herein, is changed relative to the rate of proliferation of a population of control cells, such as a population of TNFRSF- expressing cells not contacted with the agonistic or antagonistic TNFRSF antibody or antigen-binding fragment thereof. A change in the rate of proliferation may manifest, for example, as a change (e.g., an increase or decrease) in the quantity of cells of interest in a subject or sample over a given time period, such as a change in the quantity of cells of interest in a subject or sample of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more, over a given time period. Additionally or alternatively, change of cell proliferation may be evidenced by a finding that the rate at which cells of interest (e.g., TNFRSF- expressing cells contacted with an agonistic or antagonistic TNFRSF antibody or antigen-binding fragment thereof described herein) are dividing is changed (e.g., increased or decreased), e.g., by %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more, relative to the rate at which control cells (e.g., TNFRSF- expressing cells not contacted with the agonistic or antagonistic TNFRSF antibody or antigen-binding fragment thereof) are dividing.

[0559] As used herein, the term “pharmacokinetic profile” refers to the absorption, distribution, metabolism, and clearance of a drug over time following administration of the drug to a subject.

[0560] As used herein, the terms “TNFRSF natural ligand,” “endogenous TNFRSF ligand,” and “TNFRSF endogenous ligand” refer to an endogenous ligand of a TNFRSF member protein that may form a TNFRSF ligand-TNFRSF member protein complex and induce the formation of the active, homotrimeric conformation of the TNFRSF member protein. Exemplary TNFRSF ligand-TNFRSF member protein complexes may include, but are not limited to, the CD40L-CD40 complex, the 4- 1 BBL-4-1 BB complex, the CD70-CD27 complex, the CD153-CD30 complex, the N-APP-DR6 complex, the EDA-A1-EDAR complex, the FasL-Fas complex, the GITRL-GITR complex, the LT-a- HVEM complex, the LT-p (TNF-C)- LT-p receptor complex, the NGF-NGFR complex, the TRAIL-OPG complex, the OX40L-OX40 complex, the RANKL-RANK complex, the TNFa-TNFR1 complex, the TRAIL-TRAIL-R2 (TNFRSF10B) complex, the TRAIL-TRAIL-R1 (TNFRSF10A) complex, the TRAIL- TRAIL-R4 complex, the TL1 A-TRAMP complex, the EDA-A2-XEDAR complex, the FasL-DCR3 complex, the LIGHT-DCR3 complex, and the TL1 A-DCR3 complex. As used herein, the phrase “specifically binds” refers to a binding reaction which is determinative of the presence of an antigen in a heterogeneous population of proteins and other biological molecules that is recognized, e.g., by an antibody or antigen-binding fragment thereof, with particularity. An antibody or antigen-binding fragment thereof that specifically binds to an antigen will bind to the antigen with a Kd of less than 100 nM. For example, an antibody or antigen-binding fragment thereof that specifically binds to an antigen will bind to the antigen with a Kd of up to 100 nM (e.g., between 1 pM and 100 nM). An antibody or antigen-binding fragment thereof that does not exhibit specific binding to a particular antigen or epitope thereof will exhibit a Kd of greater than 100 nM (e.g., greater than 500 nm, 1 pM, 100 pM, 500 pM, or 1 mM) for that particular antigen or epitope thereof. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein or carbohydrate. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein or carbohydrate. See, Harlow & Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1988) and Harlow & Lane, Using Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1999), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.

[0561] As used herein, the terms “subject” and “patient” refer to an organism that receives treatment for a particular disease or condition as described herein (such as cancer or an infectious disease). Examples of subjects and patients include mammals, such as humans, primates, pigs, goats, rabbits, hamsters, cats, dogs, guinea pigs, members of the Bo vidae family (such as cattle, cow, bison, buffalo, elk, and yaks, among others), sheep, and horses, among others, receiving treatment for diseases or conditions, for example, cell proliferation disorders, such as cancer or infectious diseases.

[0562] As used herein, the term “transfection” refers to any of a wide variety of techniques commonly used for the introduction of an exogenous polynucleotide into a prokaryotic or eukaryotic host cell, e.g., electroporation, lipofection, calcium phosphate precipitation, diethylaminoethyl (DEAE)-dextran transfection, and the like.

[0563] As used herein, the terms “treat” or “treatment” refer to therapeutic treatment, in which the objective is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the progression of a cell proliferation disorder, such as cancer, an autoimmune disease, or an infectious disease. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e. , not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable (e.g., in particular in a subject that is not treated with a composition described herein). Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder, or those in which the condition or disorder is to be prevented. As used herein, the terms “tumor necrosis factor receptor superfamily,” “TNFR superfamily,” “TNFRS,” “TNFRSF,” or “TNFRSF members” refer to a group of type I transmembrane proteins with a carboxy-terminal intracellular domain and an amino-terminal extracellular domain characterized by a common cysteine-rich domain (CRD). The TNFR superfamily includes receptors that mediate cellular signaling due to binding by one or more ligands in the TNF superfamily. The TNFR superfamily can be divided into two subgroups: receptors containing the intracellular death domain and those lacking this domain. The death domain is an 80 amino acid motif that propagates apoptotic signal transduction cascades following receptor activation. Exemplary TNFR superfamily members that contain the intracellular death domain include TNFR1 , while TNFR2 represents a TNFR superfamily protein that does not contain this domain. Members of the TNFR superfamily include CD40, TNFR1 , TNFR2, RANK, CD30, lymphotoxin beta receptor (LT-p receptor or LT-pR), 0X40, Fas receptor, decoy receptor 3 (DCR3), CD27, 4-1 BB, death receptor 4 (DR4), death receptor 5 (DR5), decoy receptor 1 (DCR1 ), decoy receptor 2 (DCR2), osteoprotegerin, TWEAK receptor, TACI, BAFF receptor, Herpesvirus entry mediator, nerve growth factor receptor, B cell maturation antigen, glucocorticoid-induced TNFR-related protein, TROY, death receptor 6 (DR6), death receptor 3 (DR3), and ectodysplasin A2 receptor.

[0564] As used herein, the terms “TNFRSF signaling,” “TNFRSF member protein signaling,” “TNFRSF signal transduction,” “TNFRSF member protein signal transduction,” and the like, are used interchangeably and refer to the cellular events that normally occur upon activation of a TNFRSF member (e.g., TNFR2, TNFR1 , CD40, 4-1 BB, CD27, CD30, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R2 (TNFRSF10B), TRAIL-R1 (TNFRSF10A), TRAIL-R4, TRAMP, TROY, XEDAR, or DCR3) on the surface of a TNFRSF member expressing cell, such as T-reg cell, MDSC, or TNFRSF member expressing cancer cell, by an endogenous TNFRSF member ligand, such as CD40L for CD40, TNFa for TNFR1 and TNFR2, 4- 1 BBL for 4-1 BB, CD70 for CD27, CD153 for CD30, N-APP for DR6, EDA-A1 for EDAR, FasL for Fas, GITRL for GITR, LTa for HVEM, LT-p (TNF-C) for LT-p receptor complex, NGF for NGFR, TRAIL for OPG, OX40L for 0X40, RANKL for RANK, TRAIL for TRAIL-R2 (TNFRSF1 OB), TRAIL-R1 (TNFRSF1 OA), and TRAIL-R4, TL1 A for TRAMP, EDA-A2 for XEDAR, or FasL, LIGHT, and TL1 A for DCR3, among others. TNFRSF member signaling may be evidenced by a finding that expression is increased for one or more genes selected from the group consisting of CHUK, NFKBIE, NFKBIA, MAP3K1 1 , TRAF2, TRAF3, relB, and clAP2 / BIRC3. TNFRSF member signaling is considered to be “inhibited” as used herein when the expression (and / or post-translational modification in the event that such a modification is required for activity of the encoded protein) of one or more, or all, of the foregoing genes is decreased in a TNFRSF member expressing cell upon contacting the cell with an agent, such as an agonistic or antagonistic TNFRSF antibody or antigen-binding fragment thereof described herein, relative to a TNFRSF member expressing cell that is not contacted with the agent (e.g., an agonistic or antagonistic TNFRSF antibody or antigen-binding fragment thereof). TNFRSF member signaling is considered to be “inhibited,” for example, when the expression or post- translational modification (e.g., phosphorylation) of one or more of CHUK, NFKBIE, NFKBIA, MAP3K11 , TRAF2, TRAF3, relB, or clAP2 / BIRC3, in a TNFRSF member expressing cell contacted with an antagonistic TNFRSF member polypeptide is decreased by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to the expression or post-translational modification (e.g., phosphorylation) of one or more of these genes in a TNFRSF member expressing cell not contacted with the antagonistic TNFRSF member polypeptide. Exemplary assays that can be used to determine expression level and phosphorylation state are known in the art and include, e.g., Western blot assays to determine protein content and quantitative reverse transcription polymerase chain reaction (RT-PCR) experiments to determine mRNA content.

[0565] As used herein, the term “vector” includes a nucleic acid vector, e.g., a DNA vector, such as a plasmid, an RNA vector, and a virus or other suitable replicon (e.g., viral vector). A variety of vectors have been developed for the delivery of polynucleotides encoding exogenous proteins into a prokaryotic or eukaryotic cell. Examples of such expression vectors are disclosed in, e.g., WO 1994 / 11026; incorporated herein by reference. Expression vectors described herein contain a polynucleotide sequence as well as, e.g., additional sequence elements used for the expression of proteins and / or the integration of these polynucleotide sequences into the genome of a mammalian cell. Certain vectors that can be used for the expression of antibodies and antibody fragments described herein include plasmids that contain regulatory sequences, such as promoter and enhancer regions, which direct gene transcription. Other useful vectors for expression of antibodies and antibody fragments contain polynucleotide sequences that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNA that results from gene transcription. These sequence elements include, e.g., 5’ and 3’ untranslated regions, internal ribosomal entry site (IRES), and polyadenylation signal site to direct efficient transcription of the gene carried on the expression vector. The expression vectors described herein may also contain a polynucleotide encoding a marker for selection of cells that contain such a vector. Examples of a suitable marker include genes that encode resistance to antibiotics, such as ampicillin, chloramphenicol, kanamycin, or nourseothricin.

[0566] As used herein, the term “VH” refers to the variable region of an immunoglobulin heavy chain of an antibody, including the heavy chain of an Fv, scFv, or Fab. The term “VL” refers to the variable region of an immunoglobulin light chain, including the light chain of an Fv, scFv, dsFv, or Fab. Antibodies (Abs) and immunoglobulins (Igs) are glycoproteins having the same structural characteristics. While antibodies exhibit binding specificity to a specific target, immunoglobulins include both antibodies and other antibody-like molecules which lack target specificity. Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each heavy chain of a native antibody has at the amino terminus a variable domain (VH) followed by a number of constant domains. Each light chain of a native antibody has a variable domain at the amino terminus (VL) and a constant domain at the carboxy terminus.

[0567] As used herein, the term “reference level” refers to a threshold level or a level in a control subject or control patient population. A reference level depends on the assay performed and can be determined by one of ordinary skill in the art. A reference level can be a baseline level or a level in the same subject measured at an earlier or later point in time. In some cases, a reference level is determined in a subject prior to or after the administration of an antibody or antigen-binding fragment thereof disclosed herein, a construct disclosed herein, a polynucleotide disclosed herein, a vector disclosed herein, a host cell disclosed herein, or a pharmaceutical composition disclosed herein. For example, some non-limiting examples of reference levels of human soluble TNFR2 include the level of human soluble TNFR2 in a subject that: has not been diagnosed as having a disease; does not present with at least two or more symptoms of a disease; or has not been administered with the anti- TNFRSF antibodies or antigen-binding fragments thereof disclosed herein.

[0568] As used herein, the term “modified antibody or antigen-binding fragment thereof” refers to an antibody or antigen-binding fragment thereof (e.g., an antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein, such as the antibodies or antigen-binding fragments thereof of the disclosure) that comprises one or more amino acid modifications (e.g., substitutions, deletions, insertions, or chemical modifications, among others). For example, the antibody or antigen-binding fragment thereof may have one or more amino acid modifications at the Fc domain. The term “unmodified antibody or antigen-binding fragment thereof” refers to an antibody or antigen-binding fragment thereof corresponding to a modified antibody or antigen-binding fragment thereof but that does not comprise the one or more amino acid modifications.

[0569] As used herein, the term “biological fluid” refers to the source of the fluid, and includes (but is not limited to) amniotic fluid, aqueous humor, blood and blood plasma (and herein blood refers to the plasma component, unless otherwise expressly stated or indicated in context), cerumen (ear wax), Cowper's fluid, chime, interstitial fluid, lymph fluids, mammalian milk, mucus, pleural fluid, pus, saliva, sebum, semen, serum, sweat tears, urine, vaginal secretion, vomit, and exudates (from wounds or lesions). In some embodiments, the biological fluid of the disclosure is serum. In some embodiments, the biological fluid of the disclosure is plasma.

[0570] As used herein, the term “immune response” includes, but is not limited to, T cell mediated and / or B cell mediated immune responses. Exemplary immune responses include T cell responses, e.g., cytokine production and cellular cytotoxicity. T-cell responses include Th1 and / or Th2 responses. In addition, the term immune response includes responses that are indirectly promoted by T cell activation, e.g., antibody production (humoral responses) and activation of cytokine responsive cells, e.g., eosinophils, macrophages. In addition, the term immune response includes immune responses that are indirectly affected by T cell activation, e.g., antibody production (humoral responses) and activation of cytokine responsive cells, e.g., macrophages. Immune cells involved in the immune response include lymphocytes, such as T cells (CD4+, CD8+, Th1 and Th2 cells, memory T cells) and B cells; antigen presenting cells (e.g., professional antigen presenting cells such as dendritic cells, macrophages, B lymphocytes, Langerhans cells, and non-professional antigen presenting cells such as keratinocytes, endothelial cells, astrocytes, fibroblasts, oligodendrocytes); natural killer (NK) cells; myeloid cells, such as macrophages, eosinophils, mast cells, basophils, and granulocytes. An immune response can also refer to any of innate immunity, humoral immunity, cellular immunity, autoimmunity, inflammatory response, and acquired (adaptive) immunity.

[0571] As used herein, the term “dose range” refers to an upper and a lower limit of an acceptable variation of the amount (e.g., dose) of an agent specified (e.g., an antibody or antigen-binding fragment thereof of the disclosure that specifically binds a TNFRSF member protein, a TNFSF member protein, CD28, or ICOS). Typically, a dose of an agent in any amount within the specified range can be administered to patients undergoing treatment.

[0572] Brief Description of the Drawings

[0573] Fig. 1 A is a graph showing the live cell count of Jeko-1 tumor cells at varying concentrations of a fully humanized TNFR2 antagonist antibody. The experiment was conducted as described in Example 1 below.

[0574] Fig. 1B is a graph showing the live cell count of Jeko-1 tumor cells at varying concentrations of a fully humanized TNFR2 antagonist antibody with reduced interaction with Fc receptor.

[0575] Fig. 2A is a graph showing the percentage of Treg cells in human T cells treated with a fully humanized TNFR2 agonist antibody. The experiment was conducted as described in Example 2 below.

[0576] Fig. 2B is a graph showing the percentage of Treg cells in human T cells treated with a fully humanized TNFR2 agonist antibody with LALA mutations in the Fc region.

[0577] Fig. 3A is a graph showing the percentage of Treg cells in human T cells treated with a human anti-human TNFR2 agonist. The experiment was conducted as described in Example 3 below.

[0578] Fig. 3B is a graph showing the percentage of Treg cells in human T cells treated with a human anti-human TNFR2 agonist with LALA mutations in the Fc region.

[0579] Fig. 3C is a graph showing the percentage of Treg cells in human T cells treated with a mouse anti-human TNFR2 agonist.

[0580] Fig. 4A is a graph showing Treg cell proliferation in response to increasing concentrations of Ab1 , a modified, humanized lgG4 anti-TNFR2 agonistic antibody with reduced Fc effector function (black circles) or a counterpart humanized IgG 1 anti-TNFR2 agonistic antibody (black squares).

[0581] Fig. 4B is a graph showing the change of the percentage of effector T cells (Teff) in total T cells in response to increasing concentrations of Ab1 (black circles) or a counterpart humanized IgG 1 anti-TNFR2 agonistic antibody (black squares). Fig. 5A is a graph showing the change of the percentage of Treg cells in total T cells in response to increasing concentrations of Ab1 .

[0582] Fig. 5B is a graph showing the change of the percentage of effector T cells (Teff) in total T cells in response to increasing concentrations of Ab1 .

[0583] Fig. 6 is a graph showing the change of the percentage of Treg cells in total T cells in response to increasing concentrations of Ab1 or a control TNFR2 agonistic antibody with intact Fc effector function. The concentration of the antibodies is shown in Log scale.

[0584] Fig. 7 is a diagram showing the two different modes of complex formation between an agonistic antibody and its target cell-surface receptor protein. The agonistic antibody may form a mono-complex with a cell-surface receptor protein, in which the antibody binds to only one cellsurface receptor protein. The mono-complex binding does not activate the cell-surface receptor, leading to low agonistic activity. Alternatively, the agonistic antibody may form a bi-complex with two adjacent cell-surface receptor proteins, in which the antibody binds to one receptor at each arm. The bi-complex binding leads to effective receptor cross-linking, potent receptor activation, and high agonistic activity.

[0585] Fig. 8 is a diagram showing the change of agonistic activity exerted by an agonistic antibody in response to increasing concentrations of the antibody.

[0586] Fig. 9 is a diagram showing the in vivo concentration of an agonistic antibody following subcutaneous (SQ) or intravenous (IV) administration of the antibody. SQ dosing ensures that antibody is at an optimal concentration over time to allow bi-complex formation, thus avoiding the lack of receptor cross-linking in IV administration due to oversaturation at peak concentration or insufficient receptor binding at trough concentration.

[0587] Detailed Description

[0588] Antibodies or antigen-binding fragments thereof of this disclosure that specifically bind human TNFRSF member proteins (e.g., TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, or DCR3, among others), TNFSF member proteins (e.g., TRAIL), CD28, or ICOS comprise one or more amino acid modifications (e.g., substitutions, deletions, insertions, or chemical modifications) at the Fc domain. Such modifications decrease an effector function (e.g., ADCC or ADCP) of the antibody or antigenbinding fragment thereof mediated by an Fc receptor (e.g., FcyRI, FcyRII, or FcyRIII) and enhance a biological activity (e.g., agonistic or antagonistic activity) of the antibody or antigen-binding fragment thereof. Anti-TNFRSF Antibodies or Antigen-Binding Fragments Thereof

[0589] Antibodies or antigen-binding fragments that specifically bind to TNFRSF member proteins (e.g., TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, or DCR3, among others) are well known in the art. The antibody or antigen-binding fragment thereof can be an agonistic antibody or antigen-binding fragment thereof, which, upon binding with a TNFRSF member protein, promotes or augments the activation of the TNFRSF member protein. Alternatively, the antibody or antigen-binding fragment thereof can be an antagonistic antibody or antigen-binding fragment thereof, which, upon binding with a TNFRSF member protein, inhibits or reduces the activation of the TNFRSF member protein.

[0590] Agonistic Anti-TNFR2 Antibodies or Antigen-Binding Fragments Thereof

[0591] In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprising one or more CDRs with amino acid sequences selected from Table 2 below, or variants thereof with up to two conservative amino acid substitutions. For example, the antibody or the antigen-binding fragment thereof may include a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 selected from Table 2.

[0592] Table 2. CDR sequences for agonistic anti-TNFR2 antibodies or antigen-binding fragments thereof. The CDR-H1 of agonistic antibodies or antigen-binding fragments thereof that specifically bind TNFR2 can tolerate a wide range of amino acid modifications. See, e.g., International Patent Application Publication No. WO 2021 / 231922, which is incorporated herein by reference. In some embodiments, the agonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprises a CDR-H1 having the amino acid sequence GXTFXXY (SEQ ID NO: 1449), in which each X is independently a naturally occurring amino acid. In some embodiments, the CDR-H1 has an amino acid sequence selected from the group consisting of GYTFXXY (SEQ ID NO: 1450), GSTFXXY (SEQ ID NO: 1451 ), GTTFXXY (SEQ ID NO: 1452), GCTFXXY (SEQ ID NO: 1453), GNTFXXY (SEQ ID NO: 1454), GQTFXXY (SEQ ID NO: 1455), GXTFSXY (SEQ ID NO: 1456), GXTFCXY (SEQ ID NO: 1457), GXTFYXY (SEQ ID NO: 1458), GXTFNXY (SEQ ID NO: 1459), GXTFQXY (SEQ ID NO: 1460), and GXTFXDY (SEQ ID NO: 1461 ), in which each X is independently a naturally occurring amino acid. In some embodiments, the CDR-H1 has the amino acid sequence of GYTFTDY (SEQ ID NO: 1413) or a variant thereof with up to two conservative amino acid substitutions. In some embodiments, the agonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 further comprises one or more of a CDR-H2 having the amino acid sequence NPNYDS (SEQ ID NO: 1414), NYDSTS (SEQ ID NO: 1420), or a variant thereof with up to two conservative amino acid substitutions; a CDR-H3 having the amino acid sequence GNSWYFDV (SEQ ID NO: 1415) or a variant thereof with up to two conservative amino acid substitutions; a CDR- L1 having the amino acid sequence SASSSVRYMY (SEQ ID NO: 1416) or a variant thereof with up to two conservative amino acid substitutions; a CDR-L2 having the amino acid sequence LTSNLAS (SEQ ID NO: 1417) or a variant thereof with up to two conservative amino acid substitutions; and a CDR-L3 having the amino acid sequence QQWSSNPLT (SEQ ID NO: 1418) or a variant thereof with up to two conservative amino acid substitutions.

[0593] Additional agonistic antibodies or antigen-binding fragments thereof that specifically bind TNFR2 may comprise one or more of:

[0594] (a) a CDR-H1 comprising the amino acid sequence of GYTFTDYNLD (SEQ ID NO: 1425), DYIMH (SEQ ID NO: 1426), or a variant thereof with up to two conservative amino acid substitutions;

[0595] (b) a CDR-H2 comprising the amino acid sequence of DINPNYDS (SEQ ID NO: 1427), WVDPEYGSTDYAEKFKK (SEQ ID NO: 1428), or a variant thereof with up to two conservative amino acid substitutions;

[0596] (c) a CDR-H3 comprising the amino acid sequence of TSYSQKFRG (SEQ ID NO: 1429), DDGSYSPFEDY (SEQ ID NO: 1430), or a variant thereof with up to two conservative amino acid substitutions;

[0597] (d) a CDR-L1 comprising an amino acid sequence selected from the group consisting of SASSSVRYMYWY (SEQ ID NO: 1431 ), KASENVVTYVS (SEQ ID NO: 1432), RSSQSLVHSNGNTYLH (SEQ ID NO: 1433), KASENVVTYVS (SEQ ID NO: 1434), QASQNINKYIA (SEQ ID NO: 1435), QNINKY (SEQ ID NO: 1436), and a variant thereof with up to two conservative amino acid substitutions;

[0598] (e) a CDR-L2 comprising an amino acid sequence selected from the group consisting of LTSNLAS (SEQ ID NO: 1437), VTSNLAS (SEQ ID NO: 1438), LTSNLGS (SEQ ID NO: 1439), GASNRTY (SEQ ID NO: 1440), IKVSNRFS (SEQ ID NO: 1441 ), DPEYGS (SEQ ID NO: 1442), YTSTLES (SEQ ID NO: 1443), YTS, and a variant thereof with up to two conservative amino acid substitutions; and

[0599] (f) a CDR-L3 comprising an amino acid sequence selected from the group consisting of QQRSNWP (SEQ ID NO: 1445), GQGYSYPYT (SEQ ID NO: 1446), SQTTHVPPT (SEQ ID NO:

[0600] 1447), LQYVNLIT (SEQ ID NO: 1448), and a variant thereof with up to two conservative amino acid substitutions.

[0601] In some embodiments, the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprising a VH and / or a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to a VH and / or a VL sequence selected from Table 3 below. In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment thereof disclosed in International Patent Application Publication Nos. WO 2020 / 102739, WO 2021 / 231922, WO 2020 / 061210, WO 2020 / 180712, WO 2021 / 055253, WO 2022 / 003690, WO 2020 / 089473, WO 2021 / 200840, or WO 2023 / 228082; incorporated herein by reference.

[0602] In some embodiments, the antibody or antigen-binding fragment thereof may be any antibody or antigen-binding fragment thereof disclosed in Examples 1 , 3, 4, 10, 13, and 16, and Tables 1 -3, 8, 11 , and 20, of International Patent Application Publication No. WO 2023 / 228082; incorporated herein by reference. The antibodies or antigen-binding fragment thereof of International Patent Application Publication No. WO 2023 / 228082 can be administered to a human subject subcutaneously and / or at a low dose, low dose range, or low dosing frequency.

[0603] Table 3. VH and VL sequences for agonistic anti-TNFR2 antibodies or antigen-binding fragments thereof.

[0604] Additional agonistic antibodies or antigen-binding fragments thereof that specifically bind

[0605] TNFR2 may comprise one or more of:

[0606] (a) a CDR-H1 comprising the amino acid sequence of GYTFTDYNL (SEQ ID NO: 7), or a variant thereof with up to two conservative amino acid substitutions;

[0607] (b) a CDR-H2 comprising the amino acid sequence of INPNYDST (SEQ ID NO: 8), or a variant thereof with up to two conservative amino acid substitutions;

[0608] (c) a CDR-H3 comprising the amino acid sequence of CARGNSWYFDV (SEQ ID NO: 9), or a variant thereof with up to two conservative amino acid substitutions; (d) a CDR-L1 comprising an amino acid sequence of SSVRY (SEQ ID NO: 10), or a variant thereof with up to two conservative amino acid substitutions;

[0609] (e) a CDR-L2 comprising an amino acid sequence of LTS, or a variant thereof with up to two conservative amino acid substitutions; and

[0610] (f) a CDR-L3 comprising an amino acid sequence of CQQWSSNPLT (SEQ ID NO: 12), or a variant thereof with up to two conservative amino acid substitutions.

[0611] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0612] (a) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to any one of SEQ ID NOs: 1486-1490; and (b) a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to any one of SEQ ID NOs: 1492-1497.

[0613] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0614] (a) a VH having the amino acid sequence of any one of SEQ ID NOs: 1486-1490; and

[0615] (b) a VL having the amino acid sequence of any one of SEQ ID NOs: 1492-1497.

[0616] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0617] (a) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1488 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1495;

[0618] (b) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1488 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1497;

[0619] (c) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1489 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1496;

[0620] (d) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1490 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1496; or

[0621] (e) a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1490 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1497.

[0622] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0623] (a) a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1495;

[0624] (b) a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1497;

[0625] (c) a VH having the amino acid sequence of SEQ ID NO: 1489 and a VL having the amino acid sequence of SEQ ID NO: 1496;

[0626] (d) a VH having the amino acid sequence of SEQ ID NO: 1490 and a VL having the amino acid sequence of SEQ ID NO: 1496; or

[0627] (e) a VH having the amino acid sequence of SEQ ID NO: 1490 and a VL having the amino acid sequence of SEQ ID NO: 1497. In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1488 and a VL having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1495.

[0628] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1495.

[0629] In some embodiments, the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is a human IgG 1 , human lgG2, human lgG3, or human lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is a human lgG4 antibody or antigen-binding fragment thereof.

[0630] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0631] (a) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to any one of SEQ ID NOs: 1498-1503; and

[0632] (b) a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to any one of SEQ ID NOs: 1504-1510.

[0633] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0634] (a) a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 1498- 1503; and

[0635] (b) a light chain having the amino acid sequence of any one of SEQ ID NOs: 1504-1510.

[0636] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0637] (a) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1498 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1504;

[0638] (b) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1508;

[0639] (c) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1510;

[0640] (d) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1502 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1509;

[0641] (e) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1503 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1509; or

[0642] (f) a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1503 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1510.

[0643] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0644] (a) a heavy chain having the amino acid sequence of SEQ ID NO: 1498 and a light chain having the amino acid sequence of SEQ ID NO: 1504;

[0645] (b) a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1508;

[0646] (c) a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1510;

[0647] (d) a heavy chain having the amino acid sequence of SEQ ID NO: 1502 and a light chain having the amino acid sequence of SEQ ID NO: 1509;

[0648] (e) a heavy chain having the amino acid sequence of SEQ ID NO: 1503 and a light chain having the amino acid sequence of SEQ ID NO: 1509; or

[0649] (f) a heavy chain having the amino acid sequence of SEQ ID NO: 1503 and a light chain having the amino acid sequence of SEQ ID NO: 1510.

[0650] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to SEQ ID NO: 1508.

[0651] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1508.

[0652] In some embodiments, the antibody or antigen-binding fragment thereof is a human lgG4 antibody or antigen-binding fragment thereof.

[0653] In some embodiments, the antibody or antigen-binding fragment thereof comprises one or more CDR sequences of antibody Ab1 . Antibody Ab1 is a modified, humanized lgG4 agonistic anti- TNFR2 antibody comprising, in the variable heavy (VH domain), the CDR-H1 of SEQ ID NO: 1413, the CDR-H2 of SEQ ID NO: 1414 or 1420, and the CDR-H3 of SEQ ID NO: 1415, and, in the variable light (VL) domain, the CDR-L1 , CDR-L2, and CDR-L3 of SEQ ID NOs: 1416, 1417, and 1418, respectively.

[0654] Antagonistic Anti-TNFR2 Antibodies or Antigen-Binding Fragments Thereof In some embodiments, the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprising one or more CDRs with amino acid sequences selected from Table 4 below, or variants thereof with up to two conservative amino acid substitutions. For example, the antibody or the antigen-binding fragment thereof may include a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 selected from Table 4.

[0655] Table 4. CDR sequences for antagonistic anti-TNFR2 antibodies or antigen-binding fragments thereof.

[0656] In some embodiments, the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprising a VH and / or a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to a VH and / or a VL sequence selected from Table 5 below. In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment thereof disclosed in International Patent Application Publication Nos. WO 2020 / 089474, WO 2021 / 200840, WO 2021 / 249542, WO 2022 / 161425, WO 2022 / 166846, or WO 2022 / 267926; incorporated herein by reference.

[0657] Table 5. VH and VL sequences for antagonistic anti-TNFR2 antibodies or antigen-binding fragments thereof. Anti-TNFR2 Antibodies or Antigen-Binding Fragments Thereof that are neither Agonistic nor Antagonistic

[0658] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds TNFR2 but is neither an agonist nor an antagonist. Such an antibody or antigen-binding fragment thereof is one that comprises one or more CDRs with amino acid sequences selected from Table 6 below, or variants thereof with up to two conservative amino acid substitutions. For example, the antibody or the antigen-binding fragment thereof may include a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 selected from Table 6.

[0659] Table 6. CDR sequences for anti-TNFR2 antibodies or antigen-binding fragments thereof that are neither agonists nor antagonists.

[0660] In some embodiments, the antibody or antigen-binding fragment thereof is neither an agonist nor an antagonist that specifically binds TNFR2 comprising a VH and / or a VL having amino acid sequences that are at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to a VH and / or a VL sequence selected from Table 7 below. In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment thereof disclosed in International Patent Application Publication No. WO 2022 / 003693; incorporated herein by reference.

[0661] Table 7. VH and VL sequences for antagonistic anti-TNFR2 antibodies or antigen-binding fragments thereof.

[0662] Antibodies or Antigen-Binding Fragments Thereof Binding Other TNFRSF Member Proteins

[0663] Antibodies or antigen-binding fragments thereof that specifically bind other TNFRSF member proteins (e.g., 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TNFR1 , TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3, among others) are also well known in the art. Each of the antibodies or antigen binding fragments described below can be made into a modified antibody or antigen-binding fragment thereof that includes a modified Fc domain, as described herein.

[0664] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds 4-1 BB disclosed in International Patent Application Publication Nos. WO 2005 / 035584, WO 2012 / 032433, WO 2017 / 205745, WO 2018 / 017761 , WO 2018 / 098370, WO 2018 / 114748, WO 2018 / 114754, WO 2018 / 127473, WO 2019 / 091436, WO 2019 / 140425, WO 2019 / 175125, WO 2019 / 196868, WO 2020 / 007817, WO 2020 / 073131 , WO 2020 / 111913, WO 2021 / 030488, WO 2021 / 089588, WO 2021 / 093753, WO 2021 / 101346, WO 2021 / 118246, WO 2021 / 132746, WO 2021 / 167915, WO 2021 / 207827, WO 2022 / 039490, WO 2022 / 148413, WO 2022 / 178114, WO 2022 / 200478, WO 2023 / 073225, WO 2023 / 110788, WO 2023 / 134657, or WO 2023 / 174140; incorporated herein by reference.

[0665] In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof comprises one or more CDR sequences of utomilumab (PF-05082566) with up to two conservative amino acid substitutions. In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of utomilumab (PF-05082566). Utomilumab (PF-05082566) and other anti-4-1 BB antibodies are disclosed, e.g., in WO 2012 / 032433; incorporated herein by reference.

[0666] In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof comprises one or more CDR sequences of urelumab (BMS-663513) with up to two conservative amino acid substitutions. In some embodiments, the anti-4-1 BB antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of urelumab (BMS-663513). Urelumab (BMS-663513) and other anti-4-1 BB antibodies are disclosed, e.g., in WO 2005 / 035584 and WO 2016 / 029073; incorporated herein by reference.

[0667] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds CD27 disclosed in International Patent Application Publication Nos. WO 2011 / 130434, WO 2010 / 001908, WO 2012 / 004367, WO 2015 / 016718, WO 2019 / 196117, or WO 2021 / 087016; incorporated herein by reference.

[0668] In some embodiments, the anti-CD27 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of varlilumab (CDX-1127) with up to two conservative amino acid substitutions. In some embodiments, the anti-CD27 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of varlilumab (CDX-1127). Varlilumab (CDX-1127) and other anti-CD27 antibodies are disclosed, e.g., in WO 2011 / 130434; incorporated herein by reference.

[0669] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds CD30 disclosed in International Patent Application Publication Nos. WO 2008 / 025020, WO 2017 / 066122, WO 2020 / 135559, WO 2007 / 040653, WO 2023 / 057571 , WO 2021 / 231568, WO 2021 / 091815, WO 2022 / 120084, WO 2021 / 155129, WO 2023 / 076989, WO 03 / 104432, WO 97 / 17374, or WO 96 / 22384; incorporated herein by reference.

[0670] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds CD40 disclosed in International Patent Application Publication Nos. WO 2017 / 004016, WO 2018 / 185045, WO 2016 / 196314, WO 2017 / 040932, WO 2017 / 184619, WO 2017 / 004006, WO 2016 / 023960, WO 2018 / 189220, WO 2014 / 207064, WO 2016 / 069919, WO 2009 / 062054, WO 2012 / 075111 , WO 2020 / 070035, WO 2007 / 075326, WO 2006 / 128103, WO 2017 / 205742, WO 2018 / 011421 , WO 2012 / 149356, WO 2014 / 070934, WO 2014 / 065402, WO 2014 / 065403, WO 2005 / 063289, WO 2010 / 104761 , WO 2021 / 081303, WO 2020 / 253722, WO 2020 / 154335, WO 2019 / 093342, WO 2018 / 017763, WO 2013 / 034904, WO 2019 / 106608, WO 2020 / 207470, WO 2018 / 088850, WO 2018 / 085533, WO 2021 / 183428, WO 2021 / 140222, WO 2019 / 057792, WO 2012 / 041635, WO 2018 / 178046, WO 2020 / 014974, WO 2020 / 065409, WO 2021 / 222188, WO 2022 / 078357, WO 2020 / 230899, WO 2020 / 230901 , WO 2019 / 204756, WO 2021 / 239968, WO 2022 / 133123, WO 2022 / 101458, WO 2022 / 251311 , WO 2023 / 274007, WO 2022 / 243261 , WO 2023 / 284714, WO 2023 / 046037, WO 03 / 040170, WO 2023 / 274201 , WO 2023 / 198194, WO 2023 / 020475, WO 2023 / 125652, WO 2022 / 037662, WO 2021 / 243422, or WO 2023 / 052581 ; incorporated herein by reference.

[0671] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of CDX-1140 with up to two conservative amino acid substitutions. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of CDX-1140. CDX-1140 and other anti-CD40 antibodies are disclosed, e.g., in WO 2017 / 184619 and Vitale et al. Cancer Immunol. Immunother. 68:233-245, 2019; incorporated herein by reference.

[0672] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of SEA-CD40 with up to two conservative amino acid substitutions. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of SEA-CD40. SEA-CD40 and other anti- CD40 antibodies are disclosed, e.g., in WO 2016 / 069919; incorporated herein by reference.

[0673] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of R07009789 with up to two conservative amino acid substitutions. In some embodiments, the anti-CD4O antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of R07009789. R07009789 and other antiCDF antibodies are disclosed, e.g., in US 7,338,660; WO 03 / 040170; and Vonderheide et al. J. Clin. Oncol. 25:876, 2007; incorporated herein by reference.

[0674] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of JNJ-64457107 (ADC1013) with up to two conservative amino acid substitutions. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of JNJ-64457107 (ADC1013). JNJ-64457107 (ADC1013) and other anti-CD40 antibodies are disclosed, e.g., in WO 2016 / 023960 and Mangsbo et al. Clin. Cancer Res. 21 :1115-1126, 2015; incorporated herein by reference.

[0675] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of APX-005M with up to two conservative amino acid substitutions. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of APX-005M. APX-005M and other anti- CD40 antibodies are disclosed, e.g., in WO 2014 / 070934 and WO 2018 / 085533; incorporated herein by reference.

[0676] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of Chi Lob 7 / 4 with up to two conservative amino acid substitutions. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of Chi Lob 7 / 4. Chi Lob 7 / 4 and other anti- CD40 antibodies are disclosed, e.g., in US 2009 / 0074711 and Johnson et al. Clin. Cancer Res. 21 :1321 -1328, 2015; incorporated herein by reference.

[0677] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds DR6 disclosed in International Patent Application Publication No. WO 2010 / 062904; incorporated herein by reference.

[0678] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds EDAR disclosed in International Patent Application Publication No. WO 2010 / 113117; incorporated herein by reference.

[0679] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds HVEM disclosed in International Patent Application Publication Nos. WO 2017 / 096189, WO 2016 / 054638, WO 2017 / 096276, WO 2017 / 087678, WO 2015 / 187835, WO 2015 / 184099, WO 2020 / 218951 , WO 2018 / 094300, WO 2006 / 105021 , WO 2018 / 185618, WO 2018 / 017889, WO 2020 / 163646, WO 2011 / 028683, WO 2018 / 158658, WO 2015 / 031667, WO 2009 / 009116, WO 2017 / 214548, WO 2018 / 091739, WO 2018 / 018039, WO 2020 / 108636, WO 2019 / 201301 , WO 2019 / 184898, WO 2022 / 240161 , WO 2023 / 175614, or WO 2021 / 178814; incorporated herein by reference.

[0680] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds GITR disclosed in International Patent Application Publication Nos. WO 2020 / 222235, WO 2014 / 184360, WO 2015 / 031667, WO 2022 / 208505, WO 2022 / 197866, or WO 2021 / 160266, WO 2006 / 105021 , WO 2011 / 028683, WO 2015 / 026684, WO 2015 / 184099, WO 2016 / 196792; incorporated herein by reference.

[0681] In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises one or more CDR sequences of TRX-518 with up to two conservative amino acid substitutions. In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of TRX-518. TRX-518 and other anti-GITR antibodies are disclosed, e.g., in US 7,812,135; US 8,388,967; US 9,028,823; WO 2006 / 105021 ; and Ponte J et al. Clinical Immunology 135:S96, 2010; incorporated herein by reference.

[0682] In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises one or more CDR sequences of MK-4166 or MK-1248 with up to two conservative amino acid substitutions. In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of MK-4166 or MK-1248. MK-4166, MK-1248, and other anti-GITR antibodies are disclosed, e.g., in US 8,709,424; WO 2011 / 028683; WO 2015 / 026684; and Mahne et al. Cancer Res. 77:1108-1118, 2017; incorporated herein by reference.

[0683] In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises one or more CDR sequences of GWN-323 with up to two conservative amino acid substitutions. In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of GWN-323. GWN-323 and other anti-GITR antibodies are disclosed, e.g., in Piha-Paul et al. J. Immunother. Cancer 9:e002863, 2021 ; incorporated herein by reference.

[0684] In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises one or more CDR sequences of INCAGN01876 with up to two conservative amino acid substitutions. In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of INCAGN01876. INCAGN01876 and other anti-GITR antibodies are disclosed, e.g., in US 10,155,818 and WO 2015 / 184099; incorporated herein by reference.

[0685] In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises one or more CDR sequences of BMS-986156 with up to two conservative amino acid substitutions. In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of BMS-986156. BMS-986156 and other anti- GITR antibodies are disclosed, e.g., in US 9,228,016 and WO 2016 / 196792; incorporated herein by reference.

[0686] In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises one or more CDR sequences of AMG-228 with up to two conservative amino acid substitutions. In some embodiments, the anti-GITR antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of AMG-228. AMG-228 and other anti-GITR antibodies are disclosed, e.g., in US 9,464,139 and WO 2015 / 031667; incorporated herein by reference.

[0687] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds 0X40 disclosed in International Patent Application Publication Nos. WO 2018 / 177220, WO 2017 / 063162, WO 2018 / 112346, WO 2017 / 096281 , WO 2017 / 096182, WO 2016 / 179517, WO 2018 / 202649, WO 2010 / 096418, WO 2013 / 008171 , WO 2013 / 068563, WO 2015 / 095423, WO 2015 / 153514, WO 2016 / 073380, WO 2016 / 081384, WO 2016 / 200836, WO 2017 / 130076, WO 2019 / 086497, WO 2018 / 031490, WO 2018 / 017888, WO 2018 / 002339, WO 2020 / 103836, WO 2007 / 062245, WO 2021 / 098851 , WO 2019 / 214624, WO 2013 / 028231 , WO 2019 / 089921 , WO 2012 / 027328, WO 2020 / 151761 , WO 2019 / 100320, WO 2020 / 259667, WO 2021 / 030488, WO 2023 / 109900, WO 2022 / 258015, WO 2022 / 178114, WO 2023 / 089079, WO 2020 / 063668, WO 2023 / 143597, WO 2020 / 119789, WO 2020 / 119793, WO 2020 / 119792, WO 2022 / 002009, or WO 2022 / 262749; incorporated herein by reference.

[0688] In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of tavolimab (MEDI0562) with up to two conservative amino acid substitutions. In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of tavolimab (MEDI0562). tavolimab (MEDI0562) and other anti-OX40 antibodies are disclosed, e.g., in WO 2015 / 095423; WO 2015 / 153514; WO 2016 / 073380; and WO 2016 / 081384; incorporated herein by reference.

[0689] In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of PF-04518600 with up to two conservative amino acid substitutions. In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of PF-04518600. PF-04518600 and other anti-OX40 antibodies are disclosed, e.g., in WO 2017 / 130076; incorporated herein by reference.

[0690] In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of BMS-986178 with up to two conservative amino acid substitutions. In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of BMS-986178. BMS-986178 and other anti- 0X40 antibodies are disclosed, e.g., in WO 2019 / 089921 ; incorporated herein by reference.

[0691] In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of MOXR-0916 with up to two conservative amino acid substitutions. In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of MOXR-0916. MOXR-0916 and other anti- 0X40 antibodies are disclosed, e.g., in WO 2016 / 200836; incorporated herein by reference.

[0692] In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of GSK-3174998 with up to two conservative amino acid substitutions. In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of GSK-3174998.

[0693] In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of INCAGN01949 with up to two conservative amino acid substitutions. In some embodiments, the anti-OX40 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of INCAGN01949. INCAGN01949 and other anti-OX40 antibodies are disclosed, e.g., in WO 2016 / 179517; incorporated herein by reference.

[0694] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds RANK disclosed in International Patent Application Publication No. WO 2020 / 113274; incorporated herein by reference.

[0695] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds a TRAIL receptor (e.g., TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), or TRAIL-R4) disclosed in International Patent Application Publication Nos. WO 2016 / 111344, WO 2017 / 028279, WO 2007 / 027713, or WO 2016 / 074245; incorporated herein by reference. Agonistic Anti-GITR Antibodies versus Agonistic Anti-TNFR2 Antibodies

[0696] GITR is a predominately immune receptor expressed on T cells and natural killer cells and is activated by its ligand, GITRL. GITRL is commonly expressed on antigen presenting cells and endothelial cells. Upon activation, GITR stimulates both acquired and innate immunity. GITR is potentially involved in the immune response to infection and tumors, and its activation may cause inflammation and graft vs host disease. Agonistic anti-GITR antibodies can be used to treat cancer but are detrimental to patients with autoimmune disease, because agonistic anti-GITR antibodies can activate effector T cells while inhibiting Treg cells.

[0697] The role of GITR in immune response is opposite to that of TNFR2. TNFR2 is an immune receptor with very limited human expression in adults. In general, only a restricted subset of Treg cells express TNFR2. The expression of TNFR2 on this subpopulation of Tregs identifies a subset with potent immune suppressive properties. TNFR2 functions to quiet the immune response, decreasing inflammation and suppressing autoimmunity. Over-activation of TNFR2 may cause cancer due to increased immune tolerance.

[0698] In addition, GITR is structurally different from TNFR2. GITR comprises only two extracellular subdomains, whereas TNFR2 comprises four extracellular subdomains (CRD1 , CRD2, CRD3, and CRD4). It is known that agonistic TNFR2 antibodies have the highest agonistic activity when binding to CRD1 and / or CRD2. The two extracellular subdomains of GITR correspond to CRD3 and CRD4 of TNFR2. Given their separate and distinct actions, anti-GITR antibodies would not be used to inform the design of an agonistic TNFR2 antibody.

[0699] Anti-TNFSF Antibodies or Antigen-Binding Fragments Thereof

[0700] Antibodies or antigen-binding fragments thereof that specifically bind TNFSF member proteins (e.g., TNF-a, TNF-p, lymphotoxin-p (LT-p), CD40L, FasL, CD30L, 4-1 BBL, CD27L, OX40L, TRAIL, LIGHT, RANKL, TWEAK, APRIL, BAFF, VEGI, EDA-A1 , EDA-A2, and GITRL, among others) are well known in the art. Each of the antibodies or antigen binding fragments described below can be made into a modified antibody or antigen-binding fragment thereof that includes a modified Fc domain, as described herein. In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds TRAIL.

[0701] CDRs of Agonisitc Antibodies or Antigen-Binding Fragments Thereof Binding TNFRSF Member Proteins

[0702] The CDR-H1 of agonistic antibodies or antigen-binding fragments thereof that bind TNFRSF member proteins (e.g., TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3) is of particular importance in the determination of the binding specificity and agonistic activity of such antibodies or antigen-binding fragments thereof. Efficient signaling of TNFRSF member proteins requires the formation of a homotrimeric receptor structure. Antibodies or antigen-binding fragments thereof that contain a particular CDR-H1 sequence that specifically binds one or more amino acid residues within the trimer interface of a TNFRSF member protein may stabilize the trimeric structure, thereby acting as an agonist of said TNFRSF member protein.

[0703] In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of X1X2X2X1X2X3X2JJJ, in which each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently Y, S, T, C, N, or Q; X3is D or E; and each J is independently a naturally occurring amino acid or is absent. For example, each amino acid residue of a particular CDR-H1 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof, namely GYTFTDY (SEQ ID NO: 1413), can be substituted by amino acids with a similar physiochemical property (e.g., polarity, electric charge, acidity, or alkalinity), as shown in Table 8 below.

[0704] Table 8. Acceptable amino acid substitutions of an exemplary CDR-H1 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof.

[0705] In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of GYTFTZ1Z2JJJ (SEQ ID NO: 1480), in which Z1is D or T; Z2is Y, F, or L; and each J is independently a naturally occurring amino acid or is absent. It is known in the art that an antibody comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1480 binds human TNFR2 and exerts agonistic activity. For example, International Patent Application Publication No. WO 2020 / 061210 teaches that an antibody comprising a CDR-H1 having the amino acid sequence of GYTFTTF (SEQ ID NO: 31 ), GYTFTTFGMS (SEQ ID NO: 37), or GYTFTTFG (SEQ ID NO: 73) is an agonistic antibody that binds human TNFR2. International Patent Application Publication No. WO 2021 / 141907 teaches that an antibody comprising a CDR-H1 having the amino acid sequence of GYTFTDYY (SEQ ID NO: 325) is an agonistic antibody that binds human TNFR2. International Patent Application Publication No. WO 2022 / 003690 teaches that an antibody comprising a CDR-H1 having the amino acid sequence of GYTFTDLG (SEQ ID NO: 481 ) is an agonistic antibody that binds human TNFR2. In some embodiments, the agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0706] In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413) or a variant thereof with one or more conservative amino acid substitutions. In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413) or a variant thereof with up to two conservative amino acid substitutions. In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413). In some embodiments, the agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0707] In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of X1X2X2X3X1, in which each X1is independently D or E; each X2is independently Y, S, T, C, N, or Q; and X3is L, A, V, G, I, M, W, F, or P. For example, each amino acid residue of a particular CDR-H1 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof, namely DYNLD (SEQ ID NO: 1541 ), can be substituted by amino acids with a similar physiochemical property (e.g., polarity, electric charge, acidity, or alkalinity), as shown in Table 9 below.

[0708] Table 9. Acceptable amino acid substitutions of an exemplary CDR-H1 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof.

[0709] In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of DYNLD (SEQ ID NO: 1541 ) or a variant thereof with one or more conservative amino acid substitutions. In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of DYNLD (SEQ ID NO: 1541 ) or a variant thereof with up to two conservative amino acid substitutions. In some embodiments, the CDR-H1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of DYNLD (SEQ ID NO: 1541 ). In some embodiments, the agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0710] The CDR-H2, CDR-H3, CDR-L1 , CDR-L2, and CDR-L3 of agonistic antibodies or antigenbinding fragments thereof that bind TNFRSF member proteins (e.g., TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3) can tolerate significant degree of variation. Amino acid substitutions (e.g., conservative amino acid substitutions) at the CDR-H2, CDR-H3, CDR-L1 , CDR-L2, or CDR-L3 of agonistic antibodies or antigen-binding fragments thereof that bind TNFRSF member proteins do not affect the binding specificity and agonist activity of these antibodies or antigen-binding fragments thereof.

[0711] In some embodiments, the CDR-H2 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of X1X2X3X2X3X3X1X3X3X3X3X3X3X4X2X4X2, in which each X1is independently D or E; each X2is independently I, A, V, L, G, M, W, F, or P; each X3is independently N, S, T, C, Y, or Q; and each X4is independently K, R, or H. For example, each amino acid residue of a particular CDR-H2 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof, namely DINPNYDSTSYSQKFRG (SEQ ID NO: 1542), can be substituted by amino acids with a similar physiochemical property (e.g., polarity, electric charge, acidity, or alkalinity), as shown in Table 10 below.

[0712] Table 10. Acceptable amino acid substitutions of an exemplary CDR-H2 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof.

[0713] In some embodiments, the CDR-H2 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of DINPNYDSTSYSQKFRG (SEQ ID NO: 1542) or a variant thereof with one or more conservative amino acid substitutions. In some embodiments, the CDR-H2 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of DINPNYDSTSYSQKFRG (SEQ ID NO: 1542) or a variant thereof with up to two conservative amino acid substitutions. In some embodiments, the CDR-H2 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of DINPNYDSTSYSQKFRG (SEQ ID NO: 1542). In some embodiments, the agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure further comprises one or more of a CDR-H1 , a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0714] In some embodiments, the CDR-H3 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of X1X2X2X1X2X1X3X1, in which each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently N, S, T, C, Y, or Q; and X3is D or E. For example, each amino acid residue of a particular CDR-H3 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof, namely GNSWYFDV (SEQ ID NO: 1543), can be substituted by amino acids with a similar physiochemical property (e.g., polarity, electric charge, acidity, or alkalinity), as shown in Table 1 1 below. Table 11. Acceptable amino acid substitutions of an exemplary CDR-H3 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof.

[0715] In some embodiments, the CDR-H3 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1543) or a variant thereof with one or more conservative amino acid substitutions. In some embodiments, the CDR-H3 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1543) or a variant thereof with up to two conservative amino acid substitutions. In some embodiments, the CDR-H3 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1543). In some embodiments, the agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

[0716] In some embodiments, the CDR-L1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of X1X2X1X1X1X2X3X4X1X1, in which each X1is independently S, Y, T, C, N, or Q; each X2is independently A, G, V, L, I, M, W, F, or P; X3is R, H, or K; and X4is Y, A, V, I, L, M, F, or W. For example, each amino acid residue of a particular CDR-L1 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof, namely SASSSVRYNY (SEQ ID NO: 1544), can be substituted by amino acids with a similar physiochemical property (e.g., polarity, electric charge, acidity, or alkalinity), as shown in Table 12 below. Table 12. Acceptable amino acid substitutions of an exemplary CDR-L1 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof.

[0717] In some embodiments, the CDR-L1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of SASSSVRYNY (SEQ ID NO: 1544) or a variant thereof with one or more conservative amino acid substitutions. In some embodiments, the CDR-L1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of SASSSVRYNY (SEQ ID NO: 1544) or a variant thereof with up to two conservative amino acid substitutions. In some embodiments, the CDR-L1 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of SASSSVRYNY (SEQ ID NO: 1544). In some embodiments, the agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L2, and a CDR-L3 set forth in Table 2.

[0718] In some embodiments, the CDR-L2 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of X1X2X2X2X1X1X2, in which each X1is independently L, A, V, G, I, M, W, F, or P; and each X2is independently T, S, C, Y, N, or Q. For example, each amino acid residue of a particular CDR-L2 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof, namely LTSNLAS (SEQ ID NO: 1545), can be substituted by amino acids with a similar physiochemical property (e.g., polarity, electric charge, acidity, or alkalinity), as shown in Table 13 below. Table 13. Acceptable amino acid substitutions of an exemplary CDR-L2 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof.

[0719] In some embodiments, the CDR-L2 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1545) or a variant thereof with one or more conservative amino acid substitutions. In some embodiments, the CDR-L2 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1545) or a variant thereof with up to two conservative amino acid substitutions. In some embodiments, the CDR-L2 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1545). In some embodiments, the agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , and a CDR-L3 set forth in Table 2.

[0720] In some embodiments, the CDR-L3 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of X1X2X2X1X2X2X2X1X1X2, in which each X1is independently P, A, V, L, I, M, W, F, or G; and each X2is independently Q, S, T, C, N, or Y. For example, each amino acid residue of a particular CDR-L3 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof, namely PQQWSSNPLT (SEQ ID NO: 1546), can be substituted by amino acids with a similar physiochemical property (e.g., polarity, electric charge, acidity, or alkalinity), as shown in Table 14 below.

[0721] Table 14. Acceptable amino acid substitutions of an exemplary CDR-L3 sequence of an agonistic TNFR2 antibody or antigen-binding fragment thereof.

[0722] In some embodiments, the CDR-L3 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of PQQWSSNPLT (SEQ ID NO: 1546) or a variant thereof with one or more conservative amino acid substitutions. In some embodiments, the CDR-L3 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of PQQWSSNPLT (SEQ ID NO: 1546) or a variant thereof with up to two conservative amino acid substitutions. In some embodiments, the CDR-L3 of an agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure comprises the amino acid sequence of PQQWSSNPLT (SEQ ID NO: 1546). In some embodiments, the agonistic TNFR2 antibody or antigen-binding fragment thereof of the disclosure further comprises one or more of a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , and a CDR-L2 set forth in Table 2.

[0723] In some embodiments, any of the agonistic TNFR2 antibody or antigen-binding fragment thereof disclosed herein can be administered subcutaneously to a human subject. In some embodiments, any of the agonistic TNFR2 antibody or antigen-binding fragment thereof disclosed herein can be administered to a human subject at a low dose.

[0724] Cross-Reactivity of Anti-TNFSF Antibodies or Antigen-Binding Fragments Thereof with Soluble TNFRSF Member Proteins

[0725] Anti-TNFRSF antibodies or antigen-binding fragments thereof of the disclosure (e.g., antibodies or antigen-binding fragments thereof that bind a member of the TNFRSF family of proteins, such as TNFR2, TNFR1 , 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3) may have low cross-reactivity with the soluble form of the TNFRSF member protein. For example, a TNFR2 antibody or antigen-binding fragment thereof of the disclosure may have low cross-reactivity with soluble TNFR2. Such anti- TNFRSF antibodies or antigen-binding fragments thereof may have superior biological activity as compared with antibodies or antigen-binding fragments thereof that cross-react with the soluble form of the TNFRSF member protein.

[0726] It is known in the art that an agonistic antibody or antigen-binding fragment thereof that binds a TNFRSF member protein can activate the expression of the soluble form of the TNFRSF member protein. If such an agonistic antibody or antigen-binding fragment thereof cross-reacts with the soluble form of the TNFRSF member protein, the soluble form of the TNFRSF member protein can act as a decoy to neutralize the agonistic antibody or antigen-binding fragment thereof, leading to diminished agonist activity of the antibody or antigen-binding fragment thereof, and may require increased dosing amount and / or frequency of the antibody or antigen-binding fragment thereof to achieve a therapeutic effect in a subject.

[0727] In some embodiments, the modified antibody or antigen-binding fragment thereof has less than 90% (e.g., less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%) cross-reactivity with the soluble TNFRSF member protein. In some embodiments, the modified antibody or antigen-binding fragment thereof has less than 50% cross-reactivity with the soluble TNFRSF member protein. The cross-reactivity of an antibody or antigen-binding fragment thereof with an antigen can be determined using methods that are known in the art, such as by assessing the percentage homology of an antigen sequence of a protein bound by an antibody with that the sequence of a second protein. A high percentage of homology indicates that it is highly likely that the antibody cross reacts with the second protein.

[0728] Due to the low cross-reactivity of the anti-TNFRSF antibodies or antigen-binding fragments thereof of the disclosure with soluble forms of TNFRSF member proteins, the anti-TNFRSF antibodies or antigen-binding fragments thereof of the disclosure may be used (e.g., administered to a human subject) at a low dose, e.g., a dose that is lower than a typical (or art recognized) dose level of a corresponding antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is administered once every week at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg (e.g., about 0.8 mg / kg, about 0.85 mg / kg, about 0.9 mg / kg, about 0.95 mg / kg, about 1 .0 mg / kg, about 1 .05 mg / kg, about 1 .1 mg / kg, about 1.15 mg / kg, or about 1 .2 mg / kg). In some embodiments, the antibody or antigen-binding fragment thereof is administered once every two weeks at a dose of from about 1 .65 mg / kg to about 2.5 mg / kg (e.g., about 1 .65 mg / kg, about 1 .7 mg / kg, about 1 .75 mg / kg, about 1 .8 mg / kg, about 1 .85 mg / kg, about 1 .9 mg / kg, about 1 .95 mg / kg, about 2.0 mg / kg, about 2.05 mg / kg, about 2.1 mg / kg, about 2.15 mg / kg, about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, or about 2.5 mg / kg). In some embodiments, the antibody or antigen-binding fragment thereof is administered once every three weeks at a dose of from about 2.2 mg / kg to about 3.0 mg / kg (e.g., about 2.2 mg / kg, about 2.25 mg / kg, about 2.3 mg / kg, about 2.35 mg / kg, about 2.4 mg / kg, about 2.45 mg / kg, about 2.5 mg / kg, about 2.55 mg / kg, about 2.6 mg / kg, about 2.65 mg / kg, about 2.7 mg / kg, about 2.75 mg / kg, about 2.8 mg / kg, about 2.85 mg / kg, about 2.9 mg / kg, about 2.95 mg / kg, or about 3.0 mg / kg). In some embodiments, the antibody or antigen-binding fragment thereof is administered once every four weeks at a dose of from about 2.5 mg / kg to about 4.2 mg / kg (e.g., about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, or about 4.2 mg / kg).

[0729] Anti-CD28 and Anti-ICOS Antibodies or Antigen-Binding Fragments Thereof

[0730] Antibodies or antigen-binding fragments thereof that specifically bind CD28 or ICOS are well known in the art. Each of the antibodies or antigen binding fragments described below can be made into a modified antibody or antigen-binding fragment thereof that includes a modified Fc domain, as described herein.

[0731] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds CD28 disclosed in International Patent Application Publication Nos. WO 2020 / 127618, WO 2020 / 076853, WO 2016 / 185016, WO 2020 / 132066, WO 2018 / 177966, WO 2019 / 246514, WO 2010 / 007376, WO 2020 / 198009, WO 2021 / 259890, WO

[0732] 2021 / 155380, WO 2020 / 127628, WO 2021 / 260064, WO 2015 / 198147, WO 2022 / 061098, WO

[0733] 2011 / 101791 , WO 2020 / 153605, WO 2006 / 050949, WO 2020 / 132024, WO 2016 / 146702, WO

[0734] 2012 / 080351 , WO 2019 / 240934, WO 2011 / 042891 , WO 2022 / 253867, WO 2022 / 269019, WO

[0735] 2023 / 143547, WO 01 / 88159, WO 2023 / 068382, WO 2020 / 210392, WO 2023 / 126445, WO 2023 / 215498, WO 2023 / 193239, WO 2022 / 170033, WO 2022 / 094299, WO 2023 / 215799, WO 2022 / 232392, WO 2023 / 180303, WO 02 / 051871 , or WO 2023 / 031943; incorporated herein by reference.

[0736] In some embodiments, the anti-CD28 antibody or antigen-binding fragment thereof comprises one or more CDR sequences of theralizumab (TAB-08) with up to two conservative amino acid substitutions. In some embodiments, the anti-CD28 antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of theralizumab (TAB-08). Theralizumab (TAB-08) and other anti-CD28 antibodies are disclosed, e.g., in US 2006 / 0009382 and Beyersdorf et al. Ann. Rheum. Dis. 64 Suppl 4:iv91 -95, 2005; incorporated herein by reference.

[0737] In some embodiments, the antibody or antigen-binding fragment may be any antibody or antigen-binding fragment that specifically binds ICOS disclosed in International Patent Application Publication Nos. WO 2016 / 120789, WO 2016 / 154177, WO 2018 / 029474, WO 2018 / 025221 , WO 2019 / 122049, WO 2012 / 131004, WO 2020 / 102233, WO 2021 / 043961 , WO 2019 / 229614, WO 2019 / 229613, WO 2019 / 171294, WO 2020 / 260326, WO 2020 / 031087, WO 2021 / 046293, WO 2022 / 254227, WO 2020 / 086476, WO 2022 / 098910, WO 2021 / 229032, or WO 2021 / 216417; incorporated herein by reference. In some embodiments, the anti-ICOS antibody or antigen-binding fragment thereof comprises one or more CDR sequences of GSK-3359609 with up to two conservative amino acid substitutions. In some embodiments, the anti-ICOS antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of GSK-3359609. GSK-3359609 and other anti-ICOS antibodies are disclosed, e.g., in WO 2016 / 120789; incorporated herein by reference.

[0738] In some embodiments, GSK-3359609 comprises a CDR-H1 comprising the amino acid sequence of DYAMH (SEQ ID NO: 1525), a CDR-H2 comprising the amino acid sequence of LISIYSDHTNYNQKFQG (SEQ ID NO: 1526), a CDR-H3 comprising the amino acid sequence of NNYGNYGWYFDV (SEQ ID NO: 1527), a CDR-L1 comprising the amino acid sequence of SASSSVSYMH (SEQ ID NO: 1528), a CDR-L2 comprising the amino acid sequence of DTSKLAS (SEQ ID NO: 1529), and a CDR-L3 comprising the amino acid sequence of FQGSGYPYT (SEQ ID NO: 1530). In some embodiments, GSK-3359609 comprises a VH comprising the amino acid sequence of SEQ ID NO: 1531 , a VL comprising the amino acid sequence of SEQ ID NO: 1532.

[0739] In some embodiments, the anti-ICOS antibody or antigen-binding fragment thereof comprises one or more CDR sequences of JTX-2011 with up to two conservative amino acid substitutions. In some embodiments, the anti-ICOS antibody or antigen-binding fragment thereof comprises a VH and / or a VL having amino an acid sequence that is at least 80% identical (e.g., 85%, 90%, 95%, 97%, 99%, or 100% identical) to the VH and / or VL sequence of JTX-2011 . JTX-2011 and other anti-ICOS antibodies are disclosed, e.g., in WO 2016 / 154177; incorporated herein by reference.

[0740] In some embodiments, JTX-2011 comprises a CDR-H1 comprising the amino acid sequence of GFTFSDYWMD (SEQ ID NO: 1533), a CDR-H2 comprising the amino acid sequence of NIDEDGSITEYSPFVKG (SEQ ID NO: 1534), a CDR-H3 comprising the amino acid sequence of WGRFGFDS (SEQ ID NO: 1535), a CDR-L1 comprising the amino acid sequence of KSSQSLLSGSFNYLT (SEQ ID NO: 1536), a CDR-L2 comprising the amino acid sequence of YASTRHT (SEQ ID NO: 1537), and a CDR-L3 comprising the amino acid sequence of HHHYNAPPT (SEQ ID NO: 1538). In some embodiments, JTX-2011 comprises a VH comprising the amino acid sequence of SEQ ID NO: 1539, a VL comprising the amino acid sequence of SEQ ID NO: 1540.

[0741] Amino Acid Modifications at the Fc Domain

[0742] Anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof of the disclosure contain at least 50 amino acid residues of an Fc domain. Anti-TNFRSF, anti- TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof of the disclosure further contain one or more amino acid modifications (e.g., substitutions, deletions, insertions, or chemical modifications) at the Fc domain. Methods for introducing such amino acid modifications to a polypeptide (e.g., an anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibody or antigen-binding fragment thereof of the disclosure, or the Fc domain thereof) are known in the art. It is also known to a person of ordinary skill in the art that amino acid modifications at the Fc domain generally do not affect the antigen binding properties (e.g., specificity, affinity, or avidity) of an antibody or antigenbinding fragment thereof.

[0743] Human IgG Fc Domains

[0744] Humans have four IgG subtypes referred to as IgG 1 , lgG2, lgG3, and lgG4. Each of these subtypes corresponds to a distinct heavy chain constant region comprising an Fc domain. The amino acid and DNA sequences for these heavy chains constant regions are known in the art and can be accessed using the UniProt database. Exemplary amino acid sequence of human IgG 1 heavy chain constant region can be accessed using UniProt Accession No. P01857. Exemplary amino acid sequence of human lgG2 heavy chain constant region can be accessed using UniProt Accession No. P01859. Exemplary amino acid sequence of human lgG3 heavy chain constant region can be accessed using UniProt Accession No. P01860. Exemplary amino acid sequence of human lgG4 heavy chain constant region can be accessed using UniProt Accession No. P01861 . The anti- TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof of the disclosure may have an IgG 1 , lgG2, lgG3, or lgG4 subtype. In some embodiments, the anti- TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibody or antigen-binding fragment thereof of the disclosure has an lgG4 subtype. In some embodiments, the anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibody or antigen-binding fragment thereof of the disclosure is an lgG4 antibody or antigen-binding fragment thereof.

[0745] The Fc domain of human IgGs comprises a CH2 domain and a CH3 domain. The amino acid sequences of the CH2 and CH3 domains of human IgGs are relatively conserved across different IgG subtypes. Exemplary amino acid residues at each position of human IgG CH2 domains are shown in Table 15 below, and exemplary amino acid residues at each position of human IgG CH3 domains are shown in Table 16 below. It is known to a person of ordinary skill in the art that isoforms of these sequences exist, where one or more amino acid residue modifications (e.g., substitutions, deletions, or insertions) are present. Unless otherwise specified, the amino acid positions at the Fc domain are numbered according to the EU index throughout the disclosure.

[0746] Table 15. Amino acid residues at each position of human IgG CH2 domains.

[0747] Table 16. Amino acid residues at each position of human IgG CH3 domains.

[0748] Human IgG Hinge Regions

[0749] The CH1 domain and CH2 domain of a human IgG are connected with a hinge region. The amino acid sequences of the hinge regions of human IgGs are known in the art and are described in, e.g., Kabat et al, Sequences of Proteins of Immunological Interest (National Institute of Health,

[0750] Bethesda, Md. 1987), the disclosure of which is incorporated herein by reference. Exemplary amino acid residues at each position of human IgG hinge regions are shown in Table 17 below. It is known to a person of ordinary skill in the art that isoforms of these sequences exist, where one or more amino acid residue modifications (e.g., substitutions, deletions, or insertions) are present. Unless otherwise specified, the amino acid positions at the Fc domain are numbered according to the EU index throughout the disclosure.

[0751] Table 17. Amino acid residues at each position of human IgG hinge regions.

[0752] Amino Acid Modifications that Decrease or Eliminate Fc Function It has long been thought that functional antibodies (e.g., agonistic or antagonistic antibodies, such as agonistic or antagonistic antibodies that specifically bind TNFRSF members, TNFSF members, CD28, or ICOS) are more potent when they have a functional Fc receptor region. This is because the Fc region can bind to adjacent cells and thus facilitate the recruitment of effector cells. This adjacent cell-to-cell crosslinking with the antibody as the bridge is often referred to as ADCC (antibody dependent cellular cytotoxicity). This cell-to-cell crosslinking increases the signal strength of the antibody through the antigen binding regions opposite to the Fc regions, on two different cells. Also, a functional antibody usually binds a single antigen with both antigen-binding arms. Antibody engineering is commonly performed to increase the function of the Fc region of the antibody, as this was commonly expected to increase cell-to-cell crosslinking and, thus, to enhance the potency of the antibody. There are known Fc mutations for the improvement of effector functions, such as those shown in Table 18 below. It has long been thought that:

[0753] (a) strong Fc receptor function is critical for the function of the antibody;

[0754] (b) the crosslinking mediated by an antibody that has been modified to improve Fc receptor effector function is between two cells; and

[0755] (c) an antibody, such as one modified to improve Fc receptor effector function usually binds a single antigen with both antigen-binding arms.

[0756] In contrast to this traditional thinking regarding Fc receptor effector function of antibodies, I discovered a different approach to enhancing the function of antibodies and antigen-binding fragments thereof. Functional antibodies and antigen-binding fragments thereof generated by the approaches described herein (e.g., agonistic or antagonistic antibodies, such as agonistic or antagonistic antibodies that specifically bind TNFRSF members, TNFSF members, CD28, or ICOS) are unique in that the removal of the Fc receptor region from the entire antibody (or modifications that reduce, block, or ablate Fc effector function) does not have an apparent effect that alters antigenbinding and does not destroy the agonistic or antagonistic functions of the antibodies or antigenbinding fragments thereof. Receptor mapping of these antibodies shows that these antibodies consistently bind to two adjacent antigens on the same cell. These antibodies also exhibit cell- surface-only crosslinking through what is believed to be hexagonal networks - where antibodies and antigens are all on the surface of a cell. The traits of an antibody or antigen-binding fragment thereof generated using my approach include:

[0757] (a) the removal of the Fc region of the antibody (or changes that reduce, block, or eliminate Fc region effector function) does not harm the agonist or antagonist function of the antibody or antigen binding fragment thereof;

[0758] (b) the antibody or antigen-binding fragment thereof crosslinks at the cell surface, thereby pulling together two adjacent receptors; and

[0759] (c) the antibody or antigen-binding fragment thereof only exhibits single cell crosslinking at the cell surface.

[0760] Therefore, I attempted to create potent functional antibodies by testing the following hypothesis: that ADCC function-enhanced cell-surface crosslinking antibodies would be the most potent, and that ADCC function-removed cell-surface crosslinking antibodies would be weaker. The results that I obtained and disclosed herein are surprising and paradoxical to what was known in the art for years. When I removed the Fc receptor function from cell-surface crosslinking only antibodies, I created antibodies with high potency not only at very low doses but also across very wide dose ranges (e.g., the antibodies were functional at very low doses and also at very high doses).

[0761] ADCC crosslinking antibodies and cell-surface crosslinking antibodies have been characterized by (and were often limited by bi-model dose response curves, resulting in a narrow dose range when used to treat patients. When I retained cell-surface crosslinking and removed ADCC function of antibodies, the resulting antibodies no longer exhibited bi-model dose response curves. This observation suggests, surprisingly, that retained or enhanced Fc receptor function is harmful for the function of an antibody. Therefore, the present disclosure teaches that expanded dose response curves for functional antibodies are best achieved by cell-surface crosslinking only antibodies with Fc receptor inactivation.

[0762] Antibodies of the disclosure (e.g., anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof of the disclosure) with amino acid modifications (e.g., substitutions) that decrease or eliminate (e.g., inactivate) Fc function can be administered at a higher dose, at a higher dosing frequency, or across a wider dose range relative to corresponding antibodies that do not have such amino acid modifications. In some embodiments, the anti-TNFRSF, anti- TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof of the disclosure may comprise one or more amino acid modifications (e.g., substitutions, deletions, insertions, or chemical modifications) at the Fc domain that decrease or eliminate (e.g., inactivate) the function of the Fc domain. For example, the amino acid modifications may decrease or eliminate (e.g., inactivate) the binding affinity of the antibody or antigen-binding fragment thereof for an Fc receptor (e.g., FcyRI, FcyRII, or FcyRIII) and / or an effector function of the antibody or antigen-binding fragment thereof. The effector function may be one that is mediated by an Fc receptor, such as ADCC or ADCP. In some embodiments, the amino acid modifications may be located within the hinge region of the antibody or antigen-binding fragment thereof.

[0763] In some embodiments, the Fc domain is a human IgG 1 Fc domain. In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0764] (i) L235E;

[0765] (ii) L234A and L235A;

[0766] (iii) L234A, L235A, and P329G

[0767] (iv) L234E, L235F, and P331 S;

[0768] (v) D265A;

[0769] (vi) G237A;

[0770] (vii) E318A;

[0771] (viii) E233P

[0772] (ix) G236R and L328R;

[0773] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0774] (xi) N297G or N297Q, in which the amino acid positions are numbered according to the EU index. In some embodiments, the Fc domain is a human lgG2 Fc domain. In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0775] (i) D265A;

[0776] (ii) G237A;

[0777] (iii) E318A;

[0778] (iv) H268Q, V309L, A330S, and P331 S;

[0779] (v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and

[0780] (vi) N297G or N297Q, in which the amino acid positions are numbered according to the EU index.

[0781] In some embodiments, the Fc domain is a human lgG3 Fc domain. In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0782] (i) L235E;

[0783] (ii) L234A and L235A;

[0784] (iii) L234A, L235A, and P329G

[0785] (iv) L234E, L235F, and P331 S;

[0786] (v) D265A;

[0787] (vi) G237A;

[0788] (vii) E318A;

[0789] (viii) E233P

[0790] (ix) G236R and L328R;

[0791] (x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and

[0792] (xi) N297G or N297Q, in which the amino acid positions are numbered according to the EU index.

[0793] In some embodiments, the Fc domain is a human lgG4 Fc domain. In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0794] (i) L235E;

[0795] (ii) D265A;

[0796] (iii) G237A;

[0797] (iv) E318A;

[0798] (v) E233P

[0799] (vi) G236R and L328R; and

[0800] (vii) N297G or N297Q, in which the amino acid positions are numbered according to the EU index. In some embodiments, the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P (S241 P according to Kabat). In some embodiments, the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:

[0801] (i) L235E; and

[0802] (ii) F234A and L235A, in which the amino acid positions are numbered according to the EU index.

[0803] In some embodiments, the antibody or antigen-binding fragment thereof is an lgG4 antibody or antigen-binding fragment thereof. In some embodiments, the modified antibody or antigen-binding fragment thereof comprises the amino acid substitution S228P.

[0804] In some embodiments, the one or more amino acid modifications are one or more amino acid deletions. In some embodiments, the one or more amino acid deletions are deletions of all amino acid residues of the Fc domain. In some embodiments, the antibody or antigen-binding fragment thereof lacks an Fc domain. The absence of an Fc domain leads to the loss of effector function mediated by ADCC, which is dependent on the Fc domain. However, the effector function due to cell surface crosslinking of the antibody or antigen-binding fragment thereof is not affected and is a basis for the enhanced function of antibodies or antigen-binding fragments thereof described herein that lack an Fc domain or Fc effector function. The resulting antibody or antigen-binding fragment thereof binds two adjacent antigens, a function that does not involve linking of two adjacent cells by mechanisms such as ADCC. In some embodiments, the antibody or antigen-binding fragment thereof is selected from the group consisting of a single-chain Fv molecule (scFv), a diabody, a triabody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab’)2 molecule, and a tandem scFv (taFv). A person of ordinary skill in the art would expect that antibodies or antigen-binding fragments thereof lacking an Fc domain, such as the ones described herein, retain antigen binding activity, because the binding domains of the antibodies or antigen-binding fragments are still intact.

[0805] Additional amino acid modifications that decrease or eliminate (e.g., inactivate) Fc function are known in the art and can be found, e.g., in Saunders. Front. Immunol. 10:1296, 2019; incorporated herein by reference.

[0806] In certain embodiments, the modified human lgG4 Fc domain (including the lgG4 Fc hinge region) comprising an amino acid substitution of a proline (P) for the serine (S) at amino acid position 228, according to the EU index. In certain embodiments, the modified human lgG4 Fc domain comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 1547. The modified human lgG4 Fc domain can, for example, comprise the amino acid sequence of SEQ ID NO: 1547.

[0807] In certain embodiments, the modified human lgG4 Fc domain is an lgG4*01 allotype, an lgG4*02 allotype, an lgG4*03 allotype, an lgG4*05 allotype, or an lgG4*06 allotype. In certain embodiments, the modified human lgG4 Fc domain comprises a CH2 domain according to the human lgG4 amino acid sequence provided in Table 15. In certain embodiments, the modified human lgG4 Fc domain comprises a CH3 region according to the human lgG4 amino acid sequence provided in Table 16. In certain embodiments, the modified human lgG4 Fc domain comprises a hinge region according to the human lgG4 amino acid sequence provided in Table 17. In certain embodiments, the modified human lgG4 Fc domain comprises a hinge region according to the human lgG4 amino acid sequence provided in Table 17, with the exception of an amino acid substitution of a proline (P) for a serine (S) at amino acid position 228, according to the EU index. In certain embodiments, the modified human lgG4 Fc domain results in little to no effector function, i.e. , little to no antibody-dependent cellular cytotoxicity (ADCC) or antibody dependent cellular phagocytosis (ADCP). lgG4 antibodies by their nature have less effector function than IgG 1 or lgG2 antibodies. The effector function can, for example, be referred to as ADCC. lgG4 antibodies have a number of desirable traits naturally and other isotype antibodies can be modified to have these traits. lgG4 naturally, or other isotype antibodies can be modified to, have less Fc receptor function to prevent ADCC or modified to have less ability to bind complement, and, thus, kill the target cell. Also, antibodies can be modified to remove the Fc region of the antibody, thus creating Fab’2 fragments that still have both arms but no longer have any effector function. As outlined herein, mutations in the hinge of antibodies can result in different distances between the antibody arms that affects the stabilization of the cross linking for optimal agonism.

[0808] The modified lgG4 antibodies disclosed herein have the following advantageous properties. In certain embodiments, the modified lgG4 antibodies have enhanced agonism. Reference to enhanced agonism indicates the modified lgG4 antibody is less susceptible to inhibition at a higher dose compared to a corresponding antibody having greater effector function (e.g., ADCC) (e.g., an IgG 1 or lgG2 isotype or an lgG4 isotype with one or more mutations increasing ADCC). In certain embodiments, the modified human lgG4 Fc domain on the modified lgG4 antibody decreases or inactivates an effector function of the modified lgG4 antibody as compared to a control antibody (e.g., a modified human IgG 1 or lgG2 antibody which comprises an IgG 1 or lgG2 Fc domain or an unmodified lgG4 antibody which comprises an lgG4 Fc domain). The effector function can, for example, be selected from antibody dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP). In certain embodiments, the modified human lgG4 Fc domain of the modified lgG4 antibody reduces complement binding function as compared to a control antibody (e.g., a modified human IgG 1 or lgG2 antibody which comprises an IgG 1 or lgG2 Fc domain or an unmodified lgG4 antibody which comprises an lgG4 Fc domain). In certain embodiments, the modified lgG4 antibody is capable of being administered to a subject at a higher dose range and / or frequency than a control antibody (e.g., a modified human IgG 1 or lgG2 antibody which comprises an IgG 1 or lgG2 Fc domain or an unmodified lgG4 antibody which comprises an lgG4 Fc domain). In certain embodiments, the modified lgG4 antibody comprises one or more Fc substitutions further reducing or eliminating effector function (e.g., ADCC or ADCP) as compared to a corresponding antibody having an unmodified lgG4 Fc.

[0809] In certain embodiments, the modified lgG4 antibody is capable of maintaining or increasing effectiveness when administered to a subject at a higher dose range than a control antibody (e.g., a modified human lgG1 or lgG2 antibody which comprises an lgG1 or lgG2 Fc domain). Maintaining or increasing effectiveness at a higher dose can, for example, refer to maintaining or increasing the proliferation of Treg cells when administered to a subject or patient in need thereof. Maintaining or increasing the effectiveness at a higher dose can also be monitored by measuring an increase (e.g., a 1 x, 2x, 3x, or 4x increase) of soluble TNFR2 (sTNFR2) in the blood. The sTNFR2 would optimally be increased to levels at or above 2ng / ml and up to levels of 6ng / ml. The effectiveness of the modified lgG4 antibody can be maintained or increased, for example, by subcutaneous (SQ) administration. An advantage of SQ administration over intravenous (IV) administration is that SQ administration allows the correct complex formation by the modified lgG4 antibody. SQ administration can be performed at intervals as short as 3 days and up to intervals of 4 weeks.

[0810] In certain embodiments, the modified lgG4 antibody has an enhanced binding efficacy over a longer duration compared with a control antibody (e.g., a modified human IgG 1 or lgG2 antibody which comprises an IgG 1 or lgG2 Fc domain).

[0811] In certain embodiments, the modified lgG4 antibody is further conjugated to a therapeutic agent. The therapeutic agent can, for example, be selected from the group consisting of a chemotherapy agent, an immunotherapy agent, and an agonist of TNFR2.

[0812] Amino Acid Modifications that Increase Fc Function

[0813] In some embodiments, the anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof of the disclosure do not comprise any of the amino acid modifications (e.g., substitutions, deletions, insertions, or chemical modifications) at the Fc domain that increase the function of the Fc domain. For example, the amino acid modifications may increase the binding affinity of the antibody or antigen-binding fragment thereof for an Fc receptor (e.g., FcyRI, FcyRII, or FcyRI II) and / or an effector function of the antibody or antigen-binding fragment thereof. The effector function may be one that is mediated by an Fc receptor, such as ADCC or ADCP. Exemplary amino acid modifications at the Fc domain that increase Fc function are shown in Table 18 below. Additional amino acid modifications that decrease Fc function are known in the art and can be found, e.g., in Saunders. Front. Immunol. 10:1296, 2019; incorporated herein by reference.

[0814] Table 18. Amino acid modifications at the Fc domain that decrease Fc function.

[0815] Dimeric Binding of Antibodies to TNFRSF Member Protein, CD28, or ICOS

[0816] The present disclosure is based on the surprising finding that anti-TNFRSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof with amino acid modifications at the Fc domain that decrease Fc function do not lose biological activity (e.g., TNFRSF, CD28, or ICOS agonistic or antagonistic activity) when administered at a high dose or across a wide dose range. This is in direct contrast to prior publications describing methods of enhancing the activity of therapeutic antibodies by enhancing their Fc function, such as effector functions mediated by the Fc domain (e.g., ADCC or ADCP).

[0817] Therapeutic antibodies have been observed to lose activity when used at a high concentration or dose (see, e.g., Mayes et al. Nat. Rev. Drug Discov. 17:509-527, 2018; incorporated herein by reference), which limits their dose range when administered to human patients. This phenomenon is caused by monomeric binding of the antibody to its target, where only one of the two antigen-binding arms of the antibody interact with the target. It is also a result of the suboptimal clustering of antibodies due to ADCC.

[0818] The anti-TNFRSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof of the disclosure comprise amino acid modifications at the Fc domain that decrease Fc function. The lack of Fc effector function (e.g., lack of ADCC) leads to the favorable hexagonal clustering pattern of the antibodies or antigen-binding fragments and dimeric binding of the antibodies or antigen-binding fragments with a TNFRSF member protein, CD28, or ICOS, where each arm of an antibody interacts with a TNFRSF member protein, CD28, or ICOS. Nucleic Acids and Expression Systems

[0819] Anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibodies or antigen-binding fragments thereof of the disclosure can be prepared by any of a variety of established techniques. For instance, an anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibody or antigen-binding fragment thereof of the disclosure can be prepared by recombinant expression of one or more immunoglobulin light and heavy chain genes in a host cell. For instance, to express an antibody recombinantly, a host cell can be transfected with one or more recombinant expression vectors carrying DNA fragments encoding the immunoglobulin light and heavy chains of the antibody such that the light and heavy chains are expressed in the host cell and, optionally, secreted into the medium in which the host cells are cultured, from which medium the antibodies can be recovered. Standard recombinant DNA methodologies are used to obtain antibody heavy and light chain genes, incorporate these genes into recombinant expression vectors and introduce the vectors into host cells, such as those described in Molecular Cloning; A Laboratory Manual, Second Edition (Sambrook, Fritsch and Maniatis (eds), Cold Spring Harbor, N. Y., 1989), Current Protocols in Molecular Biology (Ausubel et al., eds., Greene Publishing Associates, 1989), and in U.S. Patent No. 4,816,397; incorporated herein by reference.

[0820] Vectors for Expressing Antibodies

[0821] Viral genomes provide a rich source of vectors that can be used for the efficient delivery of exogenous genes into the genome of a cell (e.g., a eukaryotic or prokaryotic cell). Viral genomes are particularly useful vectors for gene delivery because the polynucleotides contained within such genomes are typically incorporated into the genome of a target cell by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents to induce gene integration. Examples of viral vectors include a retrovirus, adenovirus (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g. measles and Sendai), positive strand RNA viruses, such as picornavirus and alphavirus, and double stranded DNA viruses including adenovirus, herpesvirus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox). Other viruses useful for delivering polynucleotides encoding antibody light and heavy chains or antibody fragments of the disclosure include Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, and hepatitis virus, for example. Examples of retroviruses include avian leukosis-sarcoma, mammalian C-type, B-type viruses, D-type viruses, HTLV-BLV group, lentivirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, In Fundamental Virology, Third Edition, B. N. Fields, et al., Eds., Lippincott-Raven Publishers, Philadelphia, 1996). Other examples include murine leukemia viruses, murine sarcoma viruses, mouse mammary tumor virus, bovine leukemia virus, feline leukemia virus, feline sarcoma virus, avian leukemia virus, human T-cell leukemia virus, baboon endogenous virus, Gibbon ape leukemia virus, Mason Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus and lentiviruses. Other examples of vectors are described, for example, in McVey et al., (U.S. Patent. No. 5,801 ,030); incorporated herein by reference.

[0822] Polynucleotide Sequence Elements

[0823] To express the anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibodies or antigenbinding fragments thereof of the disclosure, polynucleotides encoding partial or full-length light and heavy chains, or CDRs thereof, e.g., obtained as described above, can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences. The expression vector and expression control sequences are chosen to be compatible with the expression host cell used. Polynucleotides encoding, e.g., the light chain gene and the heavy chain of anti-TNFRSF, anti-TNFSF, anti-CD28, or anti-ICOS antibody or antigen-binding fragment thereof can be inserted into separate vectors, or, optionally, both polynucleotides can be incorporated into the same expression vector using established techniques described herein or known in the art.

[0824] In addition to polynucleotides encoding the heavy and light chains of an antibody (or a polynucleotide encoding a single-chain polypeptide or an antibody fragment, such as a scFv mol...

Claims

Claims1 . A method of modulating an immune response in a human subject, the method comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human tumor necrosis factor receptor superfamily (TNFRSF) member protein, wherein the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof.

2. A method of modulating an immune response in a human subject, the method comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human TNFRSF member protein, wherein the modified antibody or antigenbinding fragment thereof comprises an Fc domain with one or more amino acid modifications, and wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose and / or frequency that produces a greater modulation of the immune response relative to an unmodified antibody or antigen-binding fragment thereof administered at said dose and / or frequency.

3. The method of claim 2, wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof.

4. The method of any one of claims 1 -3, wherein the TNFRSF member protein is selected from the group consisting of TNFR2, 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TNFR1 , TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3.

5. The method of any one of claims 1 -4, wherein the method further comprises:(a) measuring a pre-treatment level of the soluble TNFRSF member protein in the serum or plasma of the human subject prior to the administration of one or more doses of the modified antibody or antigen-binding fragment thereof;(b) measuring a post-treatment level of the soluble TNFRSF member protein in the serum or plasma of the human subject after the administration of one or more doses of the modified antibody or antigen-binding fragment thereof; and / or(c) determining a reference level of the soluble TNFRSF member protein in the serum or plasma of a healthy human.

6. The method of claim 5, wherein;(a) the modified antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein, wherein:(i) the human subject has a pre-treatment level of the soluble TNFRSF member protein that is lower than or the same as the reference level of the soluble TNFRSF member protein; and / or(ii) the human subject has a post-treatment level of the soluble TNFRSF member protein that is higher than the reference level or the pre-treatment level of the soluble TNFRSF member protein, and wherein the method further comprises administering one or more additional doses of the agonistic antibody or antigen-binding fragment thereof to the human subject in one or more additional treatment periods to maintain the higher level; or(b) the modified antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein, wherein:(i) the human subject has a pre-treatment level of the soluble TNFRSF member protein that is higher than the reference level of the soluble TNFRSF member protein; and / or(ii) the human subject has a post-treatment level of the soluble TNFRSF member protein that is lower than the reference level or the pre-treatment level of the soluble TNFRSF member protein, and wherein the method further comprises administering one or more additional doses of the antagonistic antibody or antigen-binding fragment thereof to the human subject in one or more additional treatment periods to maintain the lower level.

7. The method of any one of claims 1 -6, wherein the modified antibody or antigenbinding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

8. The method of claim 7, wherein the TNFRSF member protein is TNFR2.

9. The method of claim 8, wherein the modified antibody or antigen-binding fragment thereof comprises:(a) a heavy chain complementarity determining region (CDR) 1 (CDR-H1 ) comprising the amino acid sequence of:(i) X1X2X2X1X2X3X2JJJ, wherein: each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently Y, S, T, C, N, or Q;X3is D or E; and each J is independently a naturally occurring amino acid or is absent; or(ii) X1X2X2X3X1, wherein: each X1is independently D or E;each X2is independently Y, S, T, C, N, or Q; andX3is L, A, V, G, I, M, W, F, or P;(b) a CDR-H2 comprising the amino acid sequence ofX1X2X3X2X3X3X1X3X3X3X3X3X3X4X2X4X2, wherein: each X1is independently D or E; each X2is independently I, A, V, L, G, M, W, F, or P; each X3is independently N, S, T, C, Y, or Q; and each X4is independently K, R, or H;(c) a CDR-H3 comprising the amino acid sequence of X1X2X2X1X2X1X3X1, wherein: each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently N, S, T, C, Y, or Q; andX3is D or E;(d) a light chain CDR 1 (CDR-L1 ) comprising the amino acid sequence of X1X2X1X1X1X2X3X4X1X1, wherein: each X1is independently S, Y, T, C, N, or Q; each X2is independently A, G, V, L, I, M, W, F, or P;X3is R, H, or K; andX4is Y, A, V, I, L, M, F, or W;(e) a CDR-L2 comprising the amino acid sequence of X1X2X2X2X1X1X2, wherein: each X1is independently L, A, V, G, I, M, W, F, or P; and each X2is independently T, S, C, Y, N, or Q; and / or(f) a CDR-L3 comprising the amino acid sequence of X1X2X2X1X2X2X2X1X1X2, wherein: each X1is independently P, A, V, L, I, M, W, F, or G; and each X2is independently Q, S, T, C, N, or Y.

10. The method of claim 9, wherein the CDR-H1 comprises the amino acid sequence of GYTFTZ1Z2JJJ (SEQ ID NO: 1480), wherein:Z1is D or T;Z2is Y, F, or L; and each J is independently a naturally occurring amino acid or is absent.1 1 . The method of claim 10, wherein the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413).

12. The method of any one of claims 9-1 1 , wherein the modified antibody or antigenbinding fragment thereof further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR- L2, and a CDR-L3 set forth in Table 2.

13. The method of claim 8, wherein the modified antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

14. The method of claim 8, wherein the modified antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) having amino acid sequences that are at least 80% identical to the sequences set forth in Table 3.

15. The method of claim 7, wherein the TNFRSF member protein is selected from the group consisting of CD27, CD40, GITR, 0X40, and 4-1 BB.

16. The method of claim 15, wherein the modified antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of an antibody selected from the group consisting of varlilumab (CDX-1127), CDX-1140, SEA-CD40, R07009789, JNJ-64457107 (ADC1013), APX-005M, Chi Lob 7 / 4, TRX-518, MK-4166, MK-1248, GWN-323, INCAGN01876, BMS-986156, AMG-228, tavolimab (MEDI0562), PF-04518600, BMS- 986178, MOXR-0916, GSK-3174998, INCAGN01949, utomilumab (PF-05082566), and urelumab (BMS-663513).

17. The method of claim 15, wherein the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of an antibody selected from the group consisting of varlilumab (CDX- 1127), CDX-1140, SEA-CD40, RG7009789, JNJ-64457107 (ADC1013), APX-005M, Chi Lob 7 / 4, TRX-518, MK-4166, MK-1248, GWN-323, INCAGN01876, BMS-986156, AMG-228, tavolimab (MEDI0562), PF-04518600, BMS-986178, MOXR-0916, GSK-3174998, INCAGN01949, utomilumab (PF-05082566), and urelumab (BMS-663513).

18. The method of any one of claims 7-17, wherein the human subject has a serum or plasma level of the soluble TNFRSF member protein that is lower than a reference level of the soluble TNFRSF member protein.

19. The method of any one of claims 7-18, wherein the modified antibody or antigenbinding fragment thereof exerts one or more biological activities selected from the group consisting of:(a) promoting NFKB activation;(b) inducing the proliferation of a population of T-reg cells;(c) direct killing of, or promoting the death of, a population of CD8+ T cells;(d) promoting an increase in the level of one or more mRNA molecules encoding a protein selected from the group consisting of clAP2, TRAF2, Etk, VEGFR2, PI3K, Akt, a protein involved in the angiogenic pathway, an IKK complex, RIP, NIK, MAP3K, a protein involved in the NFKB pathway, NIK, JNK, AP-1 , a MEK, MKK3, NEMO, IL2R, Foxp3, IL2, TNF, lymphotoxin a, and lymphotoxin p;(e) promoting an increase in the level of one or more proteins selected from the group consisting of clAP2, TRAF2, Etk, VEGFR2, PI3K, Akt, a protein involved in the angiogenic pathway, an IKK complex, RIP, NIK, MAP3K, a protein involved in the NFKB pathway, NIK, JNK, AP-1 , a MEK, MKK3, NEMO, IL2R, Foxp3, IL2, TNF, lymphotoxin a, and lymphotoxin p;(f) promoting an increase in the level of itaconate; and(g) promoting an increase in the level of the soluble TNFRSF member protein.

20. The method of any one of claims 1 -6, wherein the modified antibody or antigenbinding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.21 . The method of claim 20, wherein the TNFRSF member protein is TNFR2.

22. The method of claim 21 , wherein the modified antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 4.

23. The method of claim 21 , wherein the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the sequences set forth in Table 5.

24. The method of any one of claims 20-23, wherein the human subject has a serum or plasma level of the soluble TNFRSF member protein that is higher than a reference level of the soluble TNFRSF member protein.

25. The method of any one of claims 20-24, wherein the modified antibody or antigenbinding fragment thereof exerts one or more biological activities selected from the group consisting of:(a) inhibiting NFKB activation;(b) reducing or inhibiting the proliferation of a population of T-reg cells;(c) inducing the proliferation of a population of CD8+ T cells;(d) reducing or inhibiting the proliferation of a population of cancer cells;(e) inhibiting the TNFRSF member protein signaling in proliferating cells;(f) not inhibiting the TNFRSF member protein signaling in resting cells;(g) reducing or inhibiting the proliferation of a population of myeloid-derived suppressor cells (MDSCs);(h) promoting a decrease in the level of one or more mRNA molecules encoding a protein selected from the group consisting of clAP2, TRAF2, Etk, VEGFR2, PI3K, Akt, a protein involved in the angiogenic pathway, an IKK complex, RIP, NIK, MAP3K, a protein involved in the NFKB pathway, NIK, JNK, AP-1 , a MEK, MKK3, NEMO, IL2R, Foxp3, IL2, TNF, lymphotoxin a, and lymphotoxin p;(i) promoting a decrease in the level of one or more proteins selected from the group consisting of clAP2, TRAF2, Etk, VEGFR2, PI3K, Akt, a protein involved in the angiogenic pathway, an IKK complex, RIP, NIK, MAP3K, a protein involved in the NFKB pathway, NIK, JNK, AP-1 , a MEK, MKK3, NEMO, IL2R, Foxp3, IL2, TNF, lymphotoxin a, and lymphotoxin p; and(j) promoting a decrease in the level of the soluble TNFRSF member protein.

26. The method of any one of claims 1 -6, wherein the modified antibody or antigenbinding fragment thereof is neither an agonist nor an antagonist of the TNFRSF member protein.

27. The method of claim 26, wherein the TNFRSF member protein is TNFR2.

28. The method of claim 27, wherein the modified antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 6.

29. The method of claim 27, wherein the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the sequences set forth in Table 7.

30. The method of any one of claims 1 -29, wherein the modified antibody or antigenbinding fragment thereof has less than about 50% cross reactivity with the soluble TNFRSF member protein.31 . A method of modulating an immune response in a human subject, the method comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human tumor necrosis factor superfamily (TNFSF) member protein, wherein the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and wherein the modified antibody or antigen-binding fragment thereof isadministered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof.

32. A method of modulating an immune response in a human subject, the method comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds a human TNFSF member protein, wherein the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose and / or frequency that produces a greater modulation of the immune response relative to an unmodified antibody or antigen-binding fragment thereof administered at said dose and / or frequency.

33. The method of claim 31 or 32, wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof.

34. The method of any one of claims 31 -33, wherein the TNFSF member protein is TRAIL.

35. A method of modulating an immune response in a human subject, the method comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds human CD28, wherein the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof.

36. A method of modulating an immune response in a human subject, the method comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds human CD28, wherein the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose and / or frequency that produces a greater modulation of the immune response relative to an unmodified antibody or antigen-binding fragment thereof administered at said dose and / or frequency.

37. The method of claim 35 or 36, wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof.

38. The method of any one of claims 35-37, wherein the modified antibody or antigenbinding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds CD28.

39. The method of claim 38, wherein the modified antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of theralizumab (TAB-08).

40. The method of claim 38, wherein the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of theralizumab (TAB-08).41 . A method of modulating an immune response in a human subject, the method comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds human ICOS, wherein the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof.

42. A method of modulating an immune response in a human subject, the method comprising administering to the subject a modified antibody or antigen-binding fragment thereof that specifically binds human ICOS, wherein the modified antibody or antigen-binding fragment thereof comprises an Fc domain with one or more amino acid modifications, and wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a dose and / or frequency that produces a greater modulation of the immune response relative to an unmodified antibody or antigen-binding fragment thereof administered at said dose and / or frequency.

43. The method of claim 41 or 42 wherein the modified antibody or antigen-binding fragment thereof is administered to the human subject at a higher dose and / or frequency relative to an unmodified antibody or antigen-binding fragment thereof.

44. The method of any one of claims 41 -43, wherein the modified antibody or antigenbinding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds ICOS.

45. The method of claim 44, wherein the modified antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of GSK-3359609 or JTX-2011 .

46. The method of claim 44, wherein the modified antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of GSK-3359609 or JTX-2011 .

47. The method of any one of claims 1 -46, wherein the one or more doses of the modified antibody or antigen-binding fragment thereof is administered to the human subject in one or more treatment periods, wherein:(a) each dose comprises:(i) from about 0.1 mg to about 5000 mg of the modified antibody or antigen-binding fragment thereof; or(ii) from about 0.001 mg / kg to about 50 mg / kg of the modified antibody or antigenbinding fragment thereof; and / or(b) each treatment period lasts one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, or more.

48. The method of any one of claims 1 -47, wherein the modified antibody or antigenbinding fragment is administered to the human subject at a frequency of one or more times a month, every three weeks, every two weeks, a week, every six days, every five days, every four days, every three days, every two days, or a day.

49. The method of any one of claims 1 -48, wherein the modified antibody or antigenbinding fragment thereof is administered to the human subject at a dose of:(a) about 10 mg to about 5000 mg; or(b) about 1 mg / kg to about 50 mg / kg.

50. The method of any one of claims 1 -49, wherein the one or more amino acid modifications comprise one or more substitutions, deletions, insertions, or chemical modifications of the Fc domain.51 . The method of any one of claims 1 -50, wherein the modified antibody or antigenbinding fragment thereof is selected from the group consisting of a monoclonal antibody or antigenbinding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragmentthereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigenbinding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, and a chimeric antibody or antigen-binding fragment thereof.

52. The method of claim 51 , wherein the modified antibody or antigen-binding fragment thereof is a human, humanized, or chimeric antibody or antigen-binding fragment thereof.

53. The method of any one of claims 1 -52, wherein:(a) the one or more amino acid modifications at the Fc domain decrease the binding affinity of the modified antibody or antigen-binding fragment thereof for an Fc receptor relative to the corresponding unmodified antibody or antigen-binding fragment thereof;(b) the effector function of the modified antibody or antigen-binding fragment thereof is not dependent on antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP);(c) the one or more amino acid modifications at the Fc domain improve a biological activity of the modified antibody or antigen-binding fragment thereof relative to the corresponding unmodified antibody or antigen-binding fragment thereof;(d) the modified antibody or antigen-binding fragment thereof exhibits dimeric binding with its antigen at a high dose, wherein the modified antibody or antigen-binding fragment thereof comprises a first arm and a second arm, wherein the first arm binds to the antigen, and wherein the second arm binds to an adjacent protein; and / or(e) the modified antibody or antigen-binding fragment thereof forms a hexagonal network with its antigen at a high dose.

54. The method of claim 53, wherein:(a) the Fc receptor is selected from the group consisting of FcyRI, FcyRII, and FcyRIII;(b) the biological activity of the modified antibody or antigen-binding fragment thereof is independent of ADCC or ADCP; and / or(c) the adjacent protein is an antigen of the antibody or antigen-binding fragment thereof.

55. The method of any one of claims 1 -54, wherein the Fc domain is selected from the group consisting of an IgG Fc domain, an IgA Fc domain, an IgD Fc domain, an IgE Fc domain, and an IgM Fc domain.

56. The method of any one of claims 1 -55, wherein the Fc domain is an IgG Fc domain.

57. The method of any one of claims 1 -56, wherein the Fc domain is a human IgG 1 Fc domain.

58. The method of claim 57, wherein the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q, and wherein the amino acid positions are numbered according to the EU index.

59. The method of any one of claims 1 -56, wherein the Fc domain is a human lgG2 Fc domain.

60. The method of claim 59, wherein the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:(i) D265A;(ii) G237A;(iii) E318A;(iv) H268Q, V309L, A330S, and P331 S;(v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and(vi) N297G or N297Q, and wherein the amino acid positions are numbered according to the EU index.61 . The method of any one of claims 1 -56, wherein the Fc domain is a human lgG3 Fc domain.

62. The method of claim 61 , wherein the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q, and wherein the amino acid positions are numbered according to the EU index.

63. The method of any one of claims 1 -56, wherein the Fc domain is a human lgG4 Fc domain.

64. The method of claim 63, wherein the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:(i) L235E;(ii) D265A;(iii) G237A;(iv) E318A;(v) E233P(vi) G236R and L328R; and(vii) N297G or N297Q, and wherein the amino acid positions are numbered according to the EU index.

65. The method of claim 63, wherein the modified antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P.

66. The method of claim 65, wherein the one or more amino acid modifications are one or more amino acid substitutions selected from the group consisting of:(i) L235E; and(ii) F234A and L235A, and wherein the amino acid positions are numbered according to the EU index.

67. The method of any one of claims 1 -66, wherein the modified antibody or antigenbinding fragment thereof does not comprise any one of the amino acid substitutions set forth in Table 18, and wherein the amino acid positions are numbered according to the EU index.

68. The method of any one of claims 1 -67, wherein the modified antibody or antigenbinding fragment thereof is conjugated to a therapeutic agent.

69. The method of claim 68, wherein the therapeutic agent is selected from the group consisting of a chemotherapy agent, an immunotherapy agent, an agonist of a TNFRSF member protein, an antagonist of a TNFRSF member protein, an agonist of a TNFSF member protein, an antagonist of a TNFSF member protein, an agonist of CD28, an antagonist of CD28, an agonist of ICOS, and an antagonist of ICOS.

70. The method of any one of claims 1 -69, wherein the method comprises administering an additional therapeutic agent.71 . The method of claim 70, wherein the additional therapeutic agent is selected from the group consisting of a chemotherapy agent, an immunotherapy agent, an agonist of a TNFRSF member protein, an antagonist of a TNFRSF member protein, an agonist of a TNFSF member protein, an antagonist of a TNFSF member protein, an agonist of CD28, an antagonist of CD28, an agonist of ICOS, and an antagonist of ICOS.

72. The method of any one of claims 1 -71 , wherein the modified antibody or antigenbinding fragment thereof is administered to the human subject intravenously or subcutaneously.

73. The method of any one of claims 1 -72, wherein the method inhibits an immune response mediated by a B cell, a CD8+ T cell, or a T-reg cell in the human subject.

74. The method of any one of claims 1 -72, wherein the method promotes an immune response mediated by a B cell, a CD8+ T cell, or a T-reg cell in the human subject.

75. The method of any one of claims 1 -74, wherein the human subject is in need of a tissue or organ regeneration.

76. The method of claim 75, wherein the tissue or organ is selected from the group consisting of a pancreas, islets, salivary gland, pituitary gland, kidney, heart, lung, hematopoietic system, cranial nerves, heart, aorta, olfactory gland, ear, nerves, structures of the head, eye, thymus,tongue, bone, liver, small intestine, large intestine, gut, lung, brain, skin, peripheral nervous system, central nervous system, spinal cord, breast, embryonic structures, embryos, and testes.

77. The method of any one of claims 1 -76, wherein the method is for treating a cell proliferation disorder.

78. The method of claim 77, wherein the cell proliferation disorder is a cancer selected from the group consisting of leukemia, lymphoma, liver cancer, bone cancer, lung cancer, brain cancer, bladder cancer, gastrointestinal cancer, breast cancer, cardiac cancer, cervical cancer, uterine cancer, head and neck cancer, gallbladder cancer, laryngeal cancer, lip and oral cavity cancer, ocular cancer, melanoma, pancreatic cancer, prostate cancer, colorectal cancer, testicular cancer, and throat cancer.

79. The method of claim 77, wherein the cell proliferation disorder is cancer selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), adrenocortical carcinoma, AIDS- related lymphoma, primary central nervous system (CNS) lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, extrahepatic cancer, Ewing sarcoma family, osteosarcoma and malignant fibrous histiocytoma, central nervous system embryonal tumors, central nervous system germ cell tumors, craniopharyngioma, ependymoma, bronchial tumors, Burkitt lymphoma, carcinoid tumor, primary lymphoma, chordoma, chronic myeloproliferative neoplasms, colon cancer, extrahepatic bile duct cancer, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, fibrous histiocytoma of bone, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), testicular germ cell tumor, gestational trophoblastic disease, glioma, childhood brain stem glioma, hairy cell leukemia, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, islet cell tumors, pancreatic neuroendocrine tumors, Wilms tumor and other childhood kidney tumors, Langerhans cell histiocytosis, small cell lung cancer, cutaneous T-cell lymphoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract carcinoma, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm (e.g., multiple myeloma or refractory multiple myeloma), myelodysplastic syndromes, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma (NHL), nonsmall cell lung cancer (NSCLC), epithelial ovarian cancer, germ cell ovarian cancer, low malignant potential ovarian cancer, pancreatic neuroendocrine tumors, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary peritoneal cancer, rectalcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Kaposi sarcoma, rhabdomyosarcoma, Sezary syndrome, small intestine cancer, soft tissue sarcoma, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, urethral cancer, endometrial uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Waldenstrom macroglobulinemia.

80. The method of any one of claims 77-79, wherein the modified antibody or antigenbinding fragment thereof is:(a) an agonistic antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein selected from the group consisting of TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF1 OB), TNFR1 , Fas, CD40, CD27, 4-1 BB, 0X40, GITR, and XEDAR; or(b) an antagonistic antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein selected from the group consisting of TRAMP, NGFR, TRAIL-R4, TNFR2, HVEM, CD30, TROY, and RELT.81 . The method of claim 80, wherein the modified antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprising a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 4.

82. The method of claim 80, wherein the modified antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds TNFR2 comprising a VH and a VL having amino acid sequences that are at least 80% identical to the sequences set forth in Table 5.

83. The method of any one of claims 1 -76, wherein the method is for treating an autoimmune disease or an inflammatory disease in the human subject.

84. The method of claim 83, wherein the autoimmune disease is selected from the group consisting of Type I diabetes, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behget’s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, limited scleroderma (CREST syndrome), cold agglutinin disease, Crohn’s disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, hypothyroidism, inflammatory bowel disease, autoimmune lymphoproliferative syndrome (ALPS), idiopathic pulmonary fibrosis, idiopathicthrombocytopenia purpura (ITP) , IgA nephropathy, juvenile arthritis, lichen planus, lupus, lupus nephritis, Meniere’s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pemphigus foliaceus, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter’s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren’s syndrome, Stiff-Man syndrome, Takayasu’s arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, Wegener’s granulomatosis, Goodpasture syndrome, transplant rejection, celiac disease, esophagitis, and inflammatory CNS disorders, optionally wherein the inflammatory CNS disorder is Alzheimer’s disease.

85. The method of any one of claims 1 -76, wherein the method is for treating an infectious disease in the human subject.

86. The method of claim 85, wherein the infectious disease is caused by one or more agents selected from the group consisting of a virus, a bacterium, a fungus, and a parasite.

87. The method of claim 86, wherein the infectious disease is caused by a virus selected from the group consisting of hepatitis C virus, Yellow fever virus, Kadam virus, Kyasanur Forest disease virus, Langat virus, Omsk hemorrhagic fever virus, Powassan virus, Royal Farm virus, Karshi virus, tick-borne encephalitis virus, Neudoerfl virus, Sofjin virus, Louping ill virus, Negishi virus, Meaban virus, Saumarez Reef virus, Tyuleniy virus, Aroa virus, dengue virus, Kedougou virus, Cacipacore virus, Koutango virus, Japanese encephalitis virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Usutu virus, West Nile virus, Yaounde virus, Kokobera virus, Bagaza virus, llheus virus, Israel turkey meningoencephalo-myelitis virus, Ntaya virus, Tembusu virus, Zika virus, Banzi virus, Bouboui virus, Edge Hill virus, Jugra virus, Saboya virus, Sepik virus, Uganda S virus, Wesselsbron virus, yellow fever virus, Entebbe bat virus, Yokose virus, Apoi virus, Cowbone Ridge virus, Jutiapa virus, Modoc virus, Sal Vieja virus, San Perlita virus, Bukalasa bat virus, Carey Island virus, Dakar bat virus, Montana myotis leukoencephalitis virus, Phnom Penh bat virus, Rio Bravo virus, Tamana bat virus, cell fusing agent virus, Ippy virus, Lassa virus, lymphocytic choriomeningitis virus (LCMV), Mobala virus, Mopeia virus, Amapari virus, Flexal virus, Guanarito virus, Junin virus, Latino virus, Machupo virus, Oliveros virus, Parana virus, Pichinde virus, Pirital virus, Sabia virus, Tacaribe virus, Tamiami virus, Whitewater Arroyo virus, Chapare virus, Lujo virus, Hantaan virus, Sin Nombre virus, Dugbe virus, Bunyamwera virus, Rift Valley fever virus, La Crosse virus, California encephalitis virus, Crimean-Congo hemorrhagic fever (CCHF) virus, Ebola virus, Marburg virus, Venezuelan equine encephalitis virus (VEE), Eastern equine encephalitis virus (EEE), Western equine encephalitis virus (WEE), Sindbis virus, rubella virus, Semliki Forest virus, Ross River virus,Barmah Forest virus, O’nyong’nyong virus, chikungunya virus, smallpox virus, monkeypox virus, vaccinia virus, herpes simplex virus, human herpes virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella-Zoster virus, Kaposi’s sarcoma associated-herpesvirus (KSHV), influenza virus, severe acute respiratory syndrome (SARS) virus, rabies virus, vesicular stomatitis virus (VSV), human respiratory syncytial virus (RSV), Newcastle disease virus, hendravirus, nipahvirus, measles virus, rinderpest virus, canine distemper virus, Sendai virus, human parainfluenza virus (e.g., 1 , 2, 3, and 4), rhinovirus, mumps virus, poliovirus, human enterovirus (e.g., A, B, C, and D), hepatitis A virus, coxsackievirus, hepatitis B virus, human papilloma virus, adeno-associated virus, astrovirus, JC virus, BK virus, SV40 virus, Norwalk virus, rotavirus, human immunodeficiency virus (HIV), and human T- lymphotropic virus Types I and II.

88. The method of claim 86, wherein the infectious disease is caused by a bacterium belonging to a genus selected from the group consisting of Salmonella, Streptococcus, Bacillus, Listeria, Corynebacterium, Nocardia, Neisseria, Actinobacter, Moraxella, Enterobacteriacece, Pseudomonas, Escherichia, Klebsiella, Serratia, Enterobacter, Proteus, Salmonella, Shigella, Yersinia, Haemophilus, Bordatella, Legionella, Pasturella, Francisella, Brucella, Bartonella, Clostridium, Vibrio, Campylobacter, and Staphylococcus.

89. The method of claim 86, wherein the infectious disease is caused by a fungus belonging to a genus selected from the group consisting of Aspergillus, Candida, Malassezia, Trichosporon, Fusarium, Acremonium, Rhizopus, Mucor, Pneumocystis, and Absidia.

90. The method of claim 86, wherein the infectious disease is caused by a parasite selected from the group consisting of Entamoeba hystolytica, Giardia lamblia, Cryptosporidium muris, Trypanosomatida gambiense, Trypanosomatida rhodesiense, Trypanosomatida crusi, Leishmania mexicana, Leishmania braziliensis, Leishmania tropica, Leishmania donovani, Toxoplasma gondii, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium falciparum, Trichomonas vaginalis, and Histomonas meleagridis. Exemplary helminthic parasites include richuris trichiura, Ascaris lumbricoides, Enterobius vermicularis, Ancylostoma duodenale, Necator americanus, Strongyloides stercoralis, Wuchereria bancrofti, and Dracunculus medinensis, Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, Fasciola hepatica, Fasciola gigantica, Heterophyes, Paragonimus westermani, Taenia solium, Taenia saginata, Hymenolepis nana, and Echinococcus granulosus.91 . The method of any one of claims 1 -76, wherein the method is for treating an inflammatory disease in the human subject.

92. The method of claim 91 , wherein the inflammatory disease is selected from the group consisting of acute or chronic inflammation, cardiac fibrosis, lung fibrosis, osteoarthritis, rheumatoid arthritis, atherosclerosis, type I diabetes, type II diabetes, graft-versus-host disease, multiple sclerosis, osteomyelitis, psoriasis, Crohn’s disease, Sjogren’s syndrome, lupus erythematosus, and ulcerative colitis.

93. The method of any one of claims 1 -76, wherein the method is for treating a neurological disease or disorder in the human subject.

94. The method of claim 93, wherein the neurological disease or disorder is selected from the group consisting of a brain tumor, a brain metastasis, a brain injury, a spinal cord injury, a nerve injury, schizophrenia, epilepsy, Parkinson’s disease, autism, Huntington’s disease, stroke, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and myasthenia gravis.

95. The method of any one of claims 1 -76, wherein the method is for treating an allergy in the human subject.

96. The method of claim 95, wherein the allergy is selected from the group consisting of food allergy, seasonal allergy, pet allergy, hives, hay fever, allergic conjunctivitis, poison ivy allergy oak allergy, mold allergy, drug allergy, dust allergy, cosmetic allergy, and chemical allergy.

97. The method of any one of claims 1 -76, wherein the method is for treating a transplant rejection in the human subject.

98. The method of claim 97, wherein the transplant rejection is selected from the group consisting of skin graft rejection, bone graft rejection, vascular tissue graft rejection, ligament graft rejection, and organ graft rejection.

99. The method of claim 98, wherein the ligament graft rejection is selected from the group consisting of cricothyroid ligament graft rejection, periodontal ligament graft rejection, suspensory ligament of the lens graft rejection, palmar radiocarpal ligament graft rejection, dorsal radiocarpal ligament graft rejection, ulnar collateral ligament graft rejection, radial collateral ligament graft rejection, suspensory ligament of the breast graft rejection, anterior sacroiliac ligament graft rejection, posterior sacroiliac ligament graft rejection, sacrotuberous ligament graft rejection, sacrospinous ligament graft rejection, inferior pubic ligament graft rejection, superior pubic ligament graft rejection, anterior cruciate ligament graft rejection, lateral collateral ligament graft rejection,posterior cruciate ligament graft rejection, medial collateral ligament graft rejection, cranial cruciate ligament graft rejection, caudal cruciate ligament graft rejection, and patellar ligament graft rejection.

100. The method of claim 98, wherein the organ graft rejection is selected from the group consisting of heart graft rejection, lung graft rejection, kidney graft rejection, liver graft rejection, pancreas graft rejection, intestine graft rejection, and thymus graft rejection.101 . The method of any one of claims 1 -76, wherein the method is for treating a graft- versus-host disease in the human subject.

102. The method of claim 101 , wherein the graft-versus-host disease arises from a bone marrow transplant, or one or more blood cells selected from the group consisting of hematopoietic stem cells, common myeloid progenitor cells, common lymphoid progenitor cells, megakaryocytes, monocytes, basophils, eosinophils, neutrophils, macrophages, T cells, B cells, natural killer cells, and dendritic cells.

103. The method of any one of claims 1 -76, wherein the method is for transplantation or for regenerating a tissue or organ in the human subject.

104. The method of claim 103, wherein the tissue or organ is selected from the group consisting of pancreas, islets, salivary gland, pituitary gland, kidney, heart, lung, hematopoietic system, cranial nerves, heart, aorta, olfactory gland, ear, nerve, eye, thymus, tongue, bone, liver, small intestine, large intestine, gastrointestinal, lung, brain, skin, peripheral nervous system, CNS, spinal cord, breast, embryonic structures, embryo, and testes.

105. The method of claim 103 or 104, wherein the tissue or organ expresses the TNFRSF member protein, the TNFSF member protein, CD28, or ICOS.

106. An antibody or antigen-binding fragment thereof that specifically binds a human TNFRSF member protein, wherein the antibody or antigen-binding fragment thereof comprises at least 50 amino acid residues of an Fc domain and one or more amino acid substitutions within the Fc domain, wherein:(a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) D265A;(ii) G237A;(iii) E318A;(iv) H268Q, V309L, A330S, and P331 S;(v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and(vi) N297G or N297Q;(c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) D265A;(iii) G237A;(iv) E318A;(v) E233P(vi) G236R and L328R; and(vii) N297G or N297Q; or(e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P, the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E; and(ii) F234A and L235A, and wherein the amino acid positions are numbered according to the EU index.

107. The antibody or antigen-binding fragment thereof of claim 106, wherein the TNFRSF member protein is selected from the group consisting of 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TNFR1 , TNFR2, TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3.

108. The antibody or antigen-binding fragment thereof of claim 106 or 107, wherein the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

109. The antibody or antigen-binding fragment thereof of claim 108, wherein the TNFRSF member protein is TNFR2.

110. The antibody or antigen-binding fragment thereof of claim 109, wherein the antibody or antigen-binding fragment thereof comprises:(a) a CDR-H1 comprising the amino acid sequence of:(i) X1X2X2X1X2X3X2JJJ, wherein: each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently Y, S, T, C, N, or Q;X3is D or E; and each J is independently a naturally occurring amino acid or is absent; or(ii) X1X2X2X3X1, wherein: each X1is independently D or E; each X2is independently Y, S, T, C, N, or Q; andX3is L, A, V, G, I, M, W, F, or P;(b) a CDR-H2 comprising the amino acid sequence of X1X2X3X2X3X3X1X3X3X3X3X3X3X4X2X4X2, wherein: each X1is independently D or E; each X2is independently I, A, V, L, G, M, W, F, or P; each X3is independently N, S, T, C, Y, or Q; andeach X4is independently K, R, or H;(c) a CDR-H3 comprising the amino acid sequence of X1X2X2X1X2X1X3X1, wherein: each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently N, S, T, C, Y, or Q; andX3is D or E;(d) a CDR-L1 comprising the amino acid sequence of X1X2X1X1X1X2X3X4X1X1, wherein: each X1is independently S, Y, T, C, N, or Q; each X2is independently A, G, V, L, I, M, W, F, or P;X3is R, H, or K; andX4is Y, A, V, I, L, M, F, or W;(e) a CDR-L2 comprising the amino acid sequence of X1X2X2X2X1X1X2, wherein: each X1is independently L, A, V, G, I, M, W, F, or P; and each X2is independently T, S, C, Y, N, or Q; and / or(f) a CDR-L3 comprising the amino acid sequence of X1X2X2X1X2X2X2X1X1X2, wherein: each X1is independently P, A, V, L, I, M, W, F, or G; and each X2is independently Q, S, T, C, N, or Y.

111. The antibody or antigen-binding fragment thereof of claim 110, wherein the CDR-H1 comprises the amino acid sequence of GYTFTZ1Z2JJJ (SEQ ID NO: 1480), wherein:Z1is D or T;Z2is Y, F, or L; and each J is independently a naturally occurring amino acid or is absent.

112. The antibody or antigen-binding fragment thereof of claim 111 , wherein the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413).

113. The antibody or antigen-binding fragment thereof of any one of claims 110-112, wherein the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

114. The antibody or antigen-binding fragment thereof of claim 109, wherein the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR- L2, and a CDR-L3 set forth in Table 2.

115. The antibody or antigen-binding fragment thereof of claim 109, wherein the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the sequences set forth in Table 3.

116. The antibody or antigen-binding fragment thereof of claim 108, wherein the TNFRSF member protein is selected from the group consisting of CD27, CD40, GITR, 0X40, and 4-1 BB.

117. The antibody or antigen-binding fragment thereof of claim 116, wherein the antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of an antibody selected from the group consisting of varlilumab (CDX- 1127), CDX-1140, SEA-CD40, R07009789, JNJ-64457107 (ADC1013), APX-005M, Chi Lob 7 / 4, TRX-518, MK-4166, MK-1248, GWN-323, INCAGN01876, BMS-986156, AMG-228, tavolimab (MEDI0562), PF-04518600, BMS-986178, MOXR-0916, GSK-3174998, INCAGN01949, utomilumab (PF-05082566), and urelumab (BMS-663513).

118. The antibody or antigen-binding fragment thereof of claim 116, wherein the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of an antibody selected from the group consisting of varlilumab (CDX-1127), CDX-1140, SEA-CD40, RG7009789, JNJ-64457107 (ADC1013), APX-005M, Chi Lob 7 / 4, TRX-518, MK-4166, MK-1248, GWN-323, INCAGN01876, BMS- 986156, AMG-228, tavolimab (MEDI0562), PF-04518600, BMS-986178, MOXR-0916, GSK-3174998, INCAGN01949, utomilumab (PF-05082566), and urelumab (BMS-663513).

119. The antibody or antigen-binding fragment thereof of claim 106 or 107, wherein the antibody or antigen-binding fragment thereof is an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

120. The antibody or antigen-binding fragment thereof of claim 119, wherein the TNFRSF member protein is TNFR2.121 . The antibody or antigen-binding fragment thereof of claim 120, wherein the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR- L2, and a CDR-L3 set forth in Table 4.

122. The antibody or antigen-binding fragment thereof of claim 120, wherein the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the sequences set forth in Table 5.

123. The antibody or antigen-binding fragment thereof of claim 106 or 107, wherein the antibody or antigen-binding fragment thereof is neither an agonist nor an antagonist of the TNFRSF member protein.

124. The antibody or antigen-binding fragment thereof of claim 123, wherein the TNFRSF member protein is TNFR2.

125. The antibody or antigen-binding fragment thereof of claim 124, wherein the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR- L2, and a CDR-L3 set forth in Table 6.

126. The antibody or antigen-binding fragment thereof of claim 124, wherein the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the sequences set forth in Table 7.

127. The antibody or antigen-binding fragment thereof of any one of claims 106-126, wherein the antibody or antigen-binding fragment thereof has less than about 50% cross reactivity with the soluble TNFRSF member protein.

128. An agonistic antibody or antigen-binding fragment thereof that specifically binds human TNFR2, comprising:(A) means for binding an epitope within human TNFR2, comprising:(a) a CDR-H1 comprising the amino acid sequence of:(i) X1X2X2X1X2X3X2JJJ, wherein: each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently Y, S, T, C, N, or Q;X3is D or E; and each J is independently a naturally occurring amino acid or is absent; or(ii) X1X2X2X3X1, wherein: each X1is independently D or E; each X2is independently Y, S, T, C, N, or Q; andX3is L, A, V, G, I, M, W, F, or P;(b) a CDR-H2 comprising the amino acid sequence of X1X2X3X2X3X3X1X3X3X3X3X3X3X4X2X4X2, wherein: each X1is independently D or E; each X2is independently I, A, V, L, G, M, W, F, or P; each X3is independently N, S, T, C, Y, or Q; andeach X4is independently K, R, or H;(c) a CDR-H3 comprising the amino acid sequence of X1X2X2X1X2X1X3X1, wherein: each X1is independently G, A, V, L, I, M, W, F, or P; each X2is independently N, S, T, C, Y, or Q; andX3is D or E;(d) a light chain CDR 1 (CDR-L1 ) comprising the amino acid sequence of X1X2X1X1X1X2X3X4X1X1, wherein: each X1is independently S, Y, T, C, N, or Q; each X2is independently A, G, V, L, I, M, W, F, or P;X3is R, H, or K; andX4is Y, A, V, I, L, M, F, or W;(e) a CDR-L2 comprising the amino acid sequence of X1X2X2X2X1X1X2, wherein: each X1is independently L, A, V, G, I, M, W, F, or P; and each X2is independently T, S, C, Y, N, or Q; and / or(f) a CDR-L3 comprising the amino acid sequence of X1X2X2X1X2X2X2X1X1X2, wherein: each X1is independently P, A, V, L, I, M, W, F, or G; and each X2is independently Q, S, T, C, N, or Y; and(B) an Fc domain comprising one or more amino acid substitutions, wherein:(a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) D265A;(ii) G237A;(iii) E318A;(iv) H268Q, V309L, A330S, and P331 S;(v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and(vi) N297G or N297Q;(c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) D265A;(iii) G237A;(iv) E318A;(v) E233P(vi) G236R and L328R; and(vii) N297G or N297Q; or(e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P, the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E; and(ii) F234A and L235A, and wherein the amino acid positions are numbered according to the EU index.

129. The antibody or antigen-binding fragment thereof of claim 120, wherein the CDR-H1 comprises the amino acid sequence of GYTFTZ1Z2JJJ (SEQ ID NO: 1480), wherein:Z1is D or T;Z2is Y, F, or L; and each J is independently a naturally occurring amino acid or is absent.

130. The antibody or antigen-binding fragment thereof of claim 129, wherein the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413).131 . The antibody or antigen-binding fragment thereof of any one of claims 128-130, wherein the antibody or antigen-binding fragment thereof further comprises one or more of a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3 set forth in Table 2.

132. An antibody or antigen-binding fragment thereof that specifically binds a human TNFSF member protein, wherein the antibody or antigen-binding fragment thereof comprises at least 50 amino acid residues of an Fc domain and one or more amino acid substitutions within the Fc domain, wherein:(a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) D265A;(ii) G237A;(iii) E318A;(iv) H268Q, V309L, A330S, and P331 S;(v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and(vi) N297G or N297Q;(c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) D265A;(iii) G237A;(iv) E318A;(v) E233P(vi) G236R and L328R; and(vii) N297G or N297Q; or(e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P, the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E; and(ii) F234A and L235A, and wherein the amino acid positions are numbered according to the EU index.

133. The antibody or antigen-binding fragment thereof of claim 132, wherein the TNFSF member protein is TRAIL.

134. An antibody or antigen-binding fragment thereof that specifically binds human CD28, wherein the antibody or antigen-binding fragment thereof comprises at least 50 amino acid residues of an Fc domain and one or more amino acid substitutions within the Fc domain, wherein:(a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) D265A;(ii) G237A;(iii) E318A;(iv) H268Q, V309L, A330S, and P331 S;(v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and(vi) N297G or N297Q;(c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) D265A;(iii) G237A;(iv) E318A;(v) E233P(vi) G236R and L328R; and(vii) N297G or N297Q; or(e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P, the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E; and(ii) F234A and L235A, and wherein the amino acid positions are numbered according to the EU index.

135. The antibody or antigen-binding fragment thereof of claim 134, wherein the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds CD28.

136. The antibody or antigen-binding fragment thereof of claim 135, wherein the antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of theralizumab (TAB-08).

137. The antibody or antigen-binding fragment thereof of claim 135, wherein the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of theralizumab (TAB-08).

138. An antibody or antigen-binding fragment thereof that specifically binds human ICOS, wherein the antibody or antigen-binding fragment thereof comprises at least 50 amino acid residues of an Fc domain and one or more amino acid substitutions within the Fc domain, wherein:(a) the Fc domain is a human IgG 1 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(b) the Fc domain is a human lgG2 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) D265A;(ii) G237A;(iii) E318A;(iv) H268Q, V309L, A330S, and P331 S;(v) V234A, G237A, P238S, H268A, V309L, A330S, and P331 S; and(vi) N297G or N297Q;(c) the Fc domain is a human lgG3 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) L234A and L235A;(iii) L234A, L235A, and P329G(iv) L234E, L235F, and P331 S;(v) D265A;(vi) G237A;(vii) E318A;(viii) E233P(ix) G236R and L328R;(x) L234A, L235A, G237A, P238S, H268A, A330S, and P331 S; and(xi) N297G or N297Q;(d) the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E;(ii) D265A;(iii) G237A;(iv) E318A;(v) E233P(vi) G236R and L328R; and(vii) N297G or N297Q; or(e) the antibody or antigen-binding fragment thereof comprises a human lgG4 hinge region having the amino acid substitution S228P, the Fc domain is a human lgG4 Fc domain, and the one or more amino acid substitutions are selected from the group consisting of:(i) L235E; and(ii) F234A and L235A, and wherein the amino acid positions are numbered according to the EU index.

139. The antibody or antigen-binding fragment thereof of claim 138, wherein the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds ICOS.

140. The antibody or antigen-binding fragment thereof of claim 139, wherein the antibody or antigen-binding fragment thereof comprises the CDR-H1 , the CDR-H2, the CDR-H3, the CDR-L1 , the CDR-L2, and the CDR-L3 of GSK-3359609 or JTX-2011 .141 . The antibody or antigen-binding fragment thereof of claim 139, wherein the antibody or antigen-binding fragment thereof comprises a VH and a VL having amino acid sequences that are at least 80% identical to the VH and the VL sequences of GSK-3359609 or JTX-2011 .

142. The antibody or antigen-binding fragment thereof of any one of claims 106-141 , wherein the antibody or antigen-binding fragment thereof does not comprise any one of the amino acid substitutions set forth in Table 18, and wherein the amino acid positions are numbered according to the EU index.

143. The antibody or antigen-binding fragment thereof of any one of claims 106-142, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, and a chimeric antibody or antigen-binding fragment thereof.

144. The antibody or antigen-binding fragment thereof of claim 143, wherein the antibody or antigen-binding fragment thereof is a human, humanized, or chimeric antibody or antigen-binding fragment thereof.

145. A method of producing the antibody or antigen-binding fragment thereof of any one of claims 106-144, the method comprising expressing a polynucleotide encoding the antibody or antigen-binding fragment thereof in a host cell and recovering the antibody or antigen-binding fragment thereof from host cell medium.

146. A construct comprising a first polypeptide domain and a second polypeptide domain, wherein the first polypeptide domain and the second polypeptide domain are each, independently, an antigen-binding fragment of any one of claims 106-144.

147. The construct of claim 146, wherein the first polypeptide domain and the second polypeptide domain are bound by a covalent linker.

148. The construct of claim 147, wherein the covalent linker comprises an amide bond or a disulfide bond.

149. A polynucleotide encoding the antibody or antigen-binding fragment thereof of any one of claims 106-144 or the construct of any one of claims 146-148.

150. A vector comprising the polynucleotide of claim 149.151 . The vector of claim 150, wherein the vector is an expression vector or a viral vector.

152. The vector of claim 151 , wherein:(a) the expression vector is a eukaryotic expression vector; or(b) the viral vector is selected from the group consisting of an adenovirus, retrovirus, poxvirus, adeno-associated virus, baculovirus, herpes simplex virus, and vaccinia virus.

153. The vector of claim 152, wherein:(a) the adenovirus is a serotype 1 -60 adenovirus;(b) the adenovirus is a serotype 5, 26, 35, or 48 adenovirus;(c) the retrovirus is a y-retrovirus or a lentivirus; or(d) the vaccinia virus is a modified vaccinia Ankara (MVA).

154. An isolated host cell comprising the vector of any one of claims 150-153.

155. The host cell of claim 154, wherein the host cell is a prokaryotic cell or a eukaryotic cell.

156. The host cell of claim 155, wherein the eukaryotic cell is a mammalian cell.

157. The host cell of claim 156, wherein the mammalian cell is a CHO cell.

158. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 106-144, the construct of any one of claims 146-148, the polynucleotide of claim 149, the vector of any one of claims 150-153, or the host cell of any one of claims 154-157, and a pharmaceutically acceptable carrier or excipient.

159. A method of modulating an immune response in a human subject, the method comprising administering to the subject the antibody or antigen-binding fragment thereof of any one of claims 106-144, the construct of any one of claims 146-148, the polynucleotide of claim 149, the vector of any one of claims 150-153, the host cell of any one of claims 154-157, or the pharmaceutical composition of claim 158.

160. The method of claim 159, wherein the method:(a) is for treating a cell proliferation disorder, an autoimmune disease, an infectious disease, an inflammatory disease, a neurological disease, an allergy, a transplant rejection, or a graft- versus-host disease in the human subject; or(b) is for transplantation or for regenerating a tissue or organ in the human subject.161 . The method of claim 160, wherein the method is for treating a cell proliferation disorder, and wherein the antibody or antigen-binding fragment thereof is:(a) an agonistic antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein selected from the group consisting of TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), TNFR1 , Fas, CD40, CD27, 4-1 BB, 0X40, GITR, and XEDAR; or(b) an antagonistic antibody or antigen-binding fragment thereof that specifically binds a TNFRSF member protein selected from the group consisting of TRAMP, NGFR, TRAIL-R4, TNFR2, HVEM, CD30, TROY, and RELT.

162. The method of any one of claims 159-161 , wherein:(a) the human subject has a serum or plasma level of a soluble TNFRSF member protein that is lower than or the same as a reference level of the soluble TNFRSF member protein, and the method comprising administering to the subject an agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein; or(b) the human subject has a serum or plasma level of a soluble TNFRSF member protein that is higher than a reference level of the soluble TNFRSF member protein, and the method comprising administering to the subject an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

163. The method of any one of claims 159-162, wherein the antibody or antigen-binding fragment thereof is administered to the human subject once every week at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg.

164. The method of any one of claims 159-162, wherein the antibody or antigen-binding fragment thereof is administered to the human subject once every two weeks at a dose of from about 1 .65 mg / kg to about 2.5 mg / kg.

165. The method of any one of claims 159-162, wherein the antibody or antigen-binding fragment thereof is administered to the human subject once every three weeks at a dose of from about 2.2 mg / kg to about 3.0 mg / kg.

166. The method of any one of claims 159-162, wherein the antibody or antigen-binding fragment thereof is administered to the human subject once every four weeks at a dose of from about 2.5 mg / kg to about 4.2 mg / kg.

167. A kit comprising an agent selected from the group consisting of the antibody or antigen-binding fragment thereof of any one of claims 106-144, the construct of any one of claims146-148, the polynucleotide of claim 149, the vector of any one of claims 150-153, the host cell of any one of claims 154-157, or the pharmaceutical composition of claim 158.

168. The kit of claim 167, wherein the kit further comprises:(a) instructions for transfecting the vector into a host cell;(b) instructions for expressing the antibody or antigen-binding fragment thereof or the construct in a host cell;(c) a reagent that can be used to express the antibody or antigen-binding fragment thereof or the construct in a host cell;(d) instructions for administering the agent to a human subject;(e) instructions for making or using the agent; and / or(f) instructions for determining a level of the soluble TNFRSF member protein.

169. A method comprising:(a)(i) detecting a level of a soluble TNFRSF member protein in a biological fluid from a subject, wherein the level of the soluble TNFRSF member protein in the biological fluid is higher relative to a reference level of the soluble TNFRSF member protein; and(ii) administering to the subject one or more doses of an antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein at a dosing frequency, wherein the method is for decreasing the level of the soluble TNFRSF member protein; or(b)(i) detecting a level of a soluble TNFRSF member protein in a biological fluid from a subject, wherein the level of the soluble TNFRSF member protein in the biological fluid is normal or lower relative to a reference level of the soluble TNFRSF member protein; and(ii) administering to the subject one or more doses of an agonistic antibody or antigenbinding fragment thereof that specifically binds the TNFRSF member protein at a dosing frequency, wherein the method is for augmenting the level of the soluble TNFRSF member protein.

170. The method of claim 169, wherein the decreased level of the soluble TNFRSF member protein in the human subject indicates the presence of inadequate T cell suppression and the need for more TNFR2 function such as a cell proliferation disorder, an autoimmune disease, an inflammatory disease, a neurological disease, an allergy, a transplant rejection, or a graft-versus-host disease in the human subject, optionally wherein the neurological disease is Alzheimer’s disease.171 . The method of claim 169 or 170, wherein:(i) the method comprises detecting an increased level of the soluble TNFRSF member protein in a biological fluid of the subject relative to a reference level of the soluble TNFRSF member protein, wherein the method further comprises: increasing the dosage and / or dosing frequency of the antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein; or decreasing the dosage and / or dosing frequency of the agonistic antibody or antigenbinding fragment thereof that specifically binds the TNFRSF member protein; or(ii) the method comprises detecting a normal or decreased level of the soluble TNFRSF member protein in a biological fluid of the subject relative to a reference level of the soluble TNFRSF member protein, wherein the method further comprises: increasing the dosage and / or dosing frequency of the agonistic antibody or antigenbinding fragment thereof that specifically binds the TNFRSF member protein; or decreasing the dosage and / or dosing frequency of the antagonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

172. The method of any one of claims 169-171 , wherein the TNFRSF member protein is selected from the group consisting of TNFR2, 4-1 BB, CD27, CD30, CD40, DR6, EDAR, Fas, GITR, HVEM, LT-p receptor, NGFR, OPG, 0X40, RANK, RELT (TNFRSF19L), TNFR1 , TRAIL-R1(TNFRSF10A), TRAIL-R2 (TNFRSF10B), TRAIL-R4, TRAMP, TROY, XEDAR, and DCR3, optionally wherein the TNFRSF member protein is TNFR2.

173. The method of any one of claims 169-172, wherein the antagonistic or agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein is administered to the human subject at a dosing frequency of once every week, once every two weeks, once every three weeks, or once every four weeks.

174. The method of any one of claims 169-173, wherein the antagonistic or agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein is administered to the human subject at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg, from about 1 .65 mg / kg to about 2.5 mg / kg, from about 2.2 mg / kg to about 3.0 mg / kg, or from about 2.5 mg / kg to about 4.2 mg / kg.

175. The method of any one of claims 169-174, wherein the antagonistic or agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein is administered to the human subject:(a) once every week at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg;(b) once every two weeks at a dose of from about 1 .65 mg / kg to about 2.5 mg / kg;(c) once every three weeks at a dose of from about 2.2 mg / kg to about 3.0 mg / kg; or(d) once every four weeks at a dose of from about 2.5 mg / kg to about 4.2 mg / kg.

176. The method of any one of claims 169-175, wherein the method further comprises decreasing the dose range of the antagonistic or the agonistic antibody or antigen-binding fragment thereof that specifically binds the TNFRSF member protein.

177. The method of any one of claims 169-176, wherein the method:(a) is for treating a cell proliferation disorder, an autoimmune disease, an infectious disease, an inflammatory disease, a neurological disease, an allergy, a transplant rejection, or a graft- versus-host disease in the human subject; or(b) is for transplantation or for regenerating a tissue or organ in the human subject.

178. The method of any one of claims 169-177, wherein the biological fluid is serum or plasma.

179. The method of any one of claims 169-178, wherein the reference level of the soluble TNFRSF member protein is the level of the soluble TNFRSF in the biological fluid of a healthy human.

180. The method of any one of claims 169-179, wherein the one or more doses of the antibody or antigen-binding fragment thereof is administered to the human subject in one or more treatment periods, wherein:(a) each dose comprises:(i) from about 0.1 mg to about 5000 mg of the antibody or antigen-binding fragment thereof; or(ii) from about 0.001 mg / kg to about 50 mg / kg of the antibody or antigen-binding fragment thereof; and / or(b) each treatment period lasts one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, or more.181 . The method of any one of claims 169-180, wherein the dosing frequency is one or more times a month, every three weeks, every two weeks, a week, every six days, every five days, every four days, every three days, every two days, or a day.

182. An antibody or antigen-binding fragment thereof that specifically binds human TNFR2, wherein the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3, wherein:(a) the CDR-H1 comprises the amino acid sequence of GXTFXXY (SEQ ID NO: 1449), wherein each X is independently a naturally occurring amino acid;(b) the CDR-H2 comprises the amino acid sequence of NPNYDS (SEQ ID NO: 1414), NYDSTS (SEQ ID NO: 1420), or a variant thereof with up to two conservative amino acid substitutions;(c) the CDR-H3 comprises the amino acid sequence of GNSWYFDV (SEQ ID NO: 1415) or a variant thereof with up to two conservative amino acid substitutions;(d) the CDR-L1 comprises the amino acid sequence of SASSSVRYMY (SEQ ID NO: 1416) or a variant thereof with up to two conservative amino acid substitutions;(e) the CDR-L2 comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1417) or a variant thereof with up to two conservative amino acid substitutions; and(f) the CDR-L3 comprises the amino acid sequence of QQWSSNPLT (SEQ ID NO: 1418) or a variant thereof with up to two conservative amino acid substitutions.

183. The antibody or antigen-binding fragment thereof of claim 182, wherein the CDR-H1 comprises an amino acid sequence selected from the group consisting of GYTFXXY (SEQ ID NO: 1450), GSTFXXY (SEQ ID NO: 1451 ), GTTFXXY (SEQ ID NO: 1452), GCTFXXY (SEQ ID NO: 1453), GNTFXXY (SEQ ID NO: 1454), GQTFXXY (SEQ ID NO: 1455), GXTFSXY (SEQ ID NO:1456), GXTFCXY (SEQ ID NO: 1457), GXTFYXY (SEQ ID NO: 1458), GXTFNXY (SEQ ID NO: 1459), GXTFQXY (SEQ ID NO: 1460), and GXTFXDY (SEQ ID NO: 1461 ), wherein each X is independently a naturally occurring amino acid.

184. The antibody or antigen-binding fragment thereof of claim 182 or 183, wherein the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413) or a variant thereof with up to two conservative amino acid substitutions.

185. The antibody or antigen-binding fragment thereof of any one of claims 182-184, wherein:(a) the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413);(b) the CDR-H2 comprises the amino acid sequence of NPNYDS (SEQ ID NO: 1414);(c) the CDR-H3 comprises the amino acid sequence of GNSWYFDV (SEQ ID NO:1415);(d) the CDR-L1 comprises the amino acid sequence of SASSSVRYMY (SEQ ID NO:1416);(e) the CDR-L2 comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1417); and(f) the CDR-L3 comprises the amino acid sequence of QQWSSNPLT (SEQ ID NO: 1418).

186. The antibody or antigen-binding fragment thereof of any one of claims 182-184, wherein:(a) the CDR-H1 comprises the amino acid sequence of GYTFTDY (SEQ ID NO: 1413);(b) the CDR-H2 comprises the amino acid sequence of NYDSTS (SEQ ID NO: 1420);(c) the CDR-H3 comprises the amino acid sequence of GNSWYFDV (SEQ ID NO:1415);(d) the CDR-L1 comprises the amino acid sequence of SASSSVRYMY (SEQ ID NO:1416);(e) the CDR-L2 comprises the amino acid sequence of LTSNLAS (SEQ ID NO: 1417); and(f) the CDR-L3 comprises the amino acid sequence of QQWSSNPLT (SEQ ID NO: 1418).

187. An antibody or antigen-binding fragment thereof that specifically binds human TNFR2, wherein the antibody or antigen-binding fragment thereof comprises a CDR-H1 , a CDR-H2, a CDR-H3, a CDR-L1 , a CDR-L2, and a CDR-L3, wherein:(a) the CDR-H1 comprises the amino acid sequence of GYTFTDYNLD (SEQ ID NO: 1425), DYIMH (SEQ ID NO: 1426), or a variant thereof with up to two conservative amino acid substitutions;(b) the CDR-H2 comprises the amino acid sequence of DINPNYDS (SEQ ID NO: 1427), WVDPEYGSTDYAEKFKK (SEQ ID NO: 1428), or a variant thereof with up to two conservative amino acid substitutions;(c) the CDR-H3 comprises the amino acid sequence of TSYSQKFRG (SEQ ID NO: 1429), DDGSYSPFEDY (SEQ ID NO: 1430), or a variant thereof with up to two conservative amino acid substitutions;(d) the CDR-L1 comprises an amino acid sequence selected from the group consisting of SASSSVRYMYWY (SEQ ID NO: 1431 ), KASENVVTYVS (SEQ ID NO: 1432), RSSQSLVHSNGNTYLH (SEQ ID NO: 1433), KASENVVTYVS (SEQ ID NO: 1434), QASQNINKYIA (SEQ ID NO: 1435), QNINKY (SEQ ID NO: 1436), and a variant thereof with up to two conservative amino acid substitutions;(e) the CDR-L2 comprises an amino acid sequence selected from the group consisting of LTSNLAS (SEQ ID NO: 1437), VTSNLAS (SEQ ID NO: 1438), LTSNLGS (SEQ ID NO: 1439), GASNRTY (SEQ ID NO: 1440), IKVSNRFS (SEQ ID NO: 1441 ), DPEYGS (SEQ ID NO: 1442), YTSTLES (SEQ ID NO: 1443), YTS, and a variant thereof with up to two conservative amino acid substitutions; and(f) the CDR-L3 comprises an amino acid sequence selected from the group consisting of QQRSNWP (SEQ ID NO: 1445), GQGYSYPYT (SEQ ID NO: 1446), SQTTHVPPT (SEQ ID NO:1447), LQYVNLIT (SEQ ID NO: 1448), and a variant thereof with up to two conservative amino acid substitutions.

188. The antibody or antigen-binding fragment thereof of claim 187, wherein:(a) the CDR-H1 comprises the amino acid sequence of GYTFTDYNLD (SEQ ID NO: 1425) or DYIMH (SEQ ID NO: 1426);(b) the CDR-H2 comprises the amino acid sequence of DINPNYDS (SEQ ID NO: 1427) or WVDPEYGSTDYAEKFKK (SEQ ID NO: 1428);(c) the CDR-H3 comprises the amino acid sequence of TSYSQKFRG (SEQ ID NO: 1429) or DDGSYSPFEDY (SEQ ID NO: 1430);(d) the CDR-L1 comprises an amino acid sequence selected from the group consisting of SASSSVRYMYWY (SEQ ID NO: 1431 ), KASENVVTYVS (SEQ ID NO: 1432), RSSQSLVHSNGNTYLH (SEQ ID NO: 1433), KASENVVTYVS (SEQ ID NO: 1434), QASQNINKYIA (SEQ ID NO: 1435), and QNINKY (SEQ ID NO: 1436);(e) the CDR-L2 comprises an amino acid sequence selected from the group consisting of LTSNLAS (SEQ ID NO: 1437), VTSNLAS (SEQ ID NO: 1438), LTSNLGS (SEQ ID NO: 1439),GASNRTY (SEQ ID NO: 1440), IKVSNRFS (SEQ ID NO: 1441 ), DPEYGS (SEQ ID NO: 1442), YTSTLES (SEQ ID NO: 1443), and YTS; and(f) the CDR-L3 comprises an amino acid sequence selected from the group consisting of QQRSNWP (SEQ ID NO: 1445), GQGYSYPYT (SEQ ID NO: 1446), SQTTHVPPT (SEQ ID NO: 1447), and LQYVNLIT (SEQ ID NO: 1448).

189. An antibody or antigen-binding fragment thereof that specifically binds human TNFR2, wherein the antibody or antigen-binding fragment thereof comprises:(a) a VH having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 1486-1490; and(b) a VL having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 1492-1497.

190. The antibody or antigen-binding fragment thereof of claim 189, wherein the antibody or antigen-binding fragment thereof comprises:(a) a VH having the amino acid sequence of any one of SEQ ID NOs: 1486-1490; and(b) a VL having the amino acid sequence of any one of SEQ ID NOs: 1492-1497.191 . The antibody or antigen-binding fragment thereof of claim 189, wherein the antibody or antigen binding fragment thereof comprises:(a) a VH having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1488 and a VL having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1495;(b) a VH having an amino acid sequence that is at least 80% identical to SEQ ID NO:1488 and a VL having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1497;(c) a VH having an amino acid sequence that is at least 80% identical to SEQ ID NO:1489 and a VL having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1496;(d) a VH having an amino acid sequence that is at least 80% identical to SEQ ID NO:1490 and a VL having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1496; or(e) a VH having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1490 and a VL having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1497.

192. The antibody or antigen-binding fragment thereof of claim 191 , wherein the antibody or antigen binding fragment thereof comprises:(a) a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1495;(b) a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1497;(c) a VH having the amino acid sequence of SEQ ID NO: 1489 and a VL having the amino acid sequence of SEQ ID NO: 1496;(d) a VH having the amino acid sequence of SEQ ID NO: 1490 and a VL having the amino acid sequence of SEQ ID NO: 1496; or(e) a VH having the amino acid sequence of SEQ ID NO: 1490 and a VL having the amino acid sequence of SEQ ID NO: 1497.

193. The antibody or antigen-binding fragment thereof of claim 189, wherein the antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1488 and a VL having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1495.

194. The antibody or antigen-binding fragment thereof of claim 193, wherein the antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 1488 and a VL having the amino acid sequence of SEQ ID NO: 1495.

195. The antibody or antigen-binding fragment thereof of any one of claims 189-194, wherein the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof.

196. The antibody or antigen-binding fragment thereof of any one of claims 189-194, wherein the antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof.

197. The antibody or antigen-binding fragment thereof of any one of claims 189-196, wherein the antibody or antigen-binding fragment thereof is a human IgG 1 , human lgG2, human lgG3, or human lgG4 antibody or antigen-binding fragment thereof.

198. The antibody or antigen-binding fragment thereof of claim 197, wherein the antibody or antigen-binding fragment thereof is a human lgG4 antibody or antigen-binding fragment thereof.

199. The antibody or antigen-binding fragment thereof of any one of claims 189-198, wherein the antibody or antigen-binding fragment thereof further comprises a human lgG4 Fc domain.

200. The antibody or antigen-binding fragment thereof of claim 199, wherein the human lgG4 Fc domain comprises a human lgG4 hinge region having the amino acid substitution S228P numbered according to the EU index.201 . An antibody or antigen-binding fragment thereof that specifically binds human TNFR2, wherein the antibody or antigen-binding fragment thereof comprises:(a) a heavy chain having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 1498-1503; and(b) a light chain having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 1504-1510.

202. The antibody or antigen-binding fragment thereof of claim 201 , wherein the antibody or antigen-binding fragment thereof comprises:(a) a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 1498- 1503; and(b) a light chain having the amino acid sequence of any one of SEQ ID NOs: 1504-1510.

203. The antibody or antigen-binding fragment thereof of claim 201 , wherein the antibody or antigen binding fragment thereof comprises:(a) a heavy chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1498 and a light chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1504;(b) a heavy chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1508;(c) a heavy chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1510;(d) a heavy chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1502 and a light chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1509;(e) a heavy chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1503 and a light chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1509; or(f) a heavy chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1503 and a light chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1510.

204. The antibody or antigen-binding fragment thereof of claim 203, wherein the antibody or antigen binding fragment thereof comprises:(a) a heavy chain having the amino acid sequence of SEQ ID NO: 1498 and a light chain having the amino acid sequence of SEQ ID NO: 1504;(b) a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1508;(c) a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1510;(d) a heavy chain having the amino acid sequence of SEQ ID NO: 1502 and a light chain having the amino acid sequence of SEQ ID NO: 1509;(e) a heavy chain having the amino acid sequence of SEQ ID NO: 1503 and a light chain having the amino acid sequence of SEQ ID NO: 1509; or(f) a heavy chain having the amino acid sequence of SEQ ID NO: 1503 and a light chain having the amino acid sequence of SEQ ID NO: 1510.

205. The antibody or antigen-binding fragment thereof of claim 201 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1501 and a light chain having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1508.

206. The antibody or antigen-binding fragment thereof of claim 205, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1501 and a light chain having the amino acid sequence of SEQ ID NO: 1508.

207. The antibody or antigen-binding fragment thereof of any one of claims 201 -206, wherein the antibody or antigen-binding fragment thereof is a human lgG4 antibody or antigen-binding fragment thereof.

208. The antibody or antigen-binding fragment thereof of any one of claims 182-207, wherein the antibody or antigen-binding fragment thereof is an agonistic antibody or antigen-binding fragment thereof that specifically binds human TNFR2.

209. The antibody or antigen-binding fragment thereof of any one of claims 182-208, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, abispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a single-chain Fv molecule (scFv), a diabody, a triabody, an antibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab’)2 molecule, and a tandem scFv (taFv).

210. The antibody or antigen-binding fragment thereof of claim 209, wherein the antibody or antigen-binding fragment thereof is a human, humanized, or chimeric antibody or antigen-binding fragment thereof.

211. A method of producing the antibody or antigen-binding fragment thereof of any one of claims 182-210, the method comprising expressing a polynucleotide encoding the antibody or antigen-binding fragment thereof in a host cell and recovering the antibody or antigen-binding fragment thereof from host cell medium.

212. A construct comprising a first polypeptide domain and a second polypeptide domain, wherein the first polypeptide domain and the second polypeptide domain are each, independently, an antigen-binding fragment of any one of claims 182-210.

213. The construct of claim 212, wherein the first polypeptide domain and the second polypeptide domain are bound by a covalent linker.

214. The construct of claim 213, wherein the covalent linker comprises an amide bond or a disulfide bond.

215. A polynucleotide encoding the antibody or antigen-binding fragment thereof of any one of claims 182-210 or the construct of any one of claims 212-214.

216. A vector comprising the polynucleotide of claim 215.

217. The vector of claim 216, wherein the vector is an expression vector or a viral vector.

218. The vector of claim 217, wherein:(a) the expression vector is a eukaryotic expression vector; or(b) the viral vector is selected from the group consisting of an adenovirus, retrovirus, poxvirus, adeno-associated virus, baculovirus, herpes simplex virus, and vaccinia virus.

219. The vector of claim 218, wherein:(a) the adenovirus is a serotype 1 -60 adenovirus;(b) the adenovirus is a serotype 5, 26, 35, or 48 adenovirus;(c) the retrovirus is a y-retrovirus or a lentivirus; or(d) the vaccinia virus is a modified vaccinia Ankara (MVA).

220. An isolated host cell comprising the vector of any one of claims 216-219.221 . The host cell of claim 220, wherein the host cell is a prokaryotic cell or a eukaryotic cell.

222. The host cell of claim 221 , wherein the eukaryotic cell is a mammalian cell.

223. The host cell of claim 222, wherein the mammalian cell is a CHO cell.

224. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 182-210, the construct of any one of claims 212-214, the polynucleotide of claim 215, the vector of any one of claims 216-219, or the host cell of any one of claims 220-223, and a pharmaceutically acceptable carrier or excipient.

225. A method of modulating an immune response in a human subject, the method comprising administering to the subject the antibody or antigen-binding fragment thereof of any one of claims 182-210, the construct of any one of claims 212-214, the polynucleotide of claim 215, the vector of any one of claims 216-219, the host cell of any one of claims 220-223, or the pharmaceutical composition of claim 224.

226. The method of claim 225, wherein the method:(a) is for treating a cell proliferation disorder, an autoimmune disease, an infectious disease, an inflammatory disease, a neurological disease, an allergy, a transplant rejection, or a graft- versus-host disease in the human subject; or(b) is for transplantation or for regenerating a tissue or organ in the human subject.

227. The method of claim 226, wherein the method is for treating a cancer.

228. The method of any one of claims 225-227, wherein the human subject has a serum or plasma level of soluble TNFR2 that is normal or lower than a reference level of soluble TNFR2,optionally wherein the method is for increasing the serum or plasma level of soluble TNFR2 in the human subject.

229. The method of any one of claims 225-228, wherein the method further comprises:(a) obtaining the biological fluid from the human subject;(b) detecting a normal or decreased level of soluble TNFR2 in the subject relative to a reference level of soluble TNFR2; and(c) administering to the subject one or more doses of the antibody or antigen-binding fragment thereof at a dosing frequency.

230. The method of any one of claims 229, wherein the method further comprises:(a) detecting a normal or decreased level of soluble TNFR2 in the subject relative to a reference level of soluble TNFR2, and increasing the level of soluble TNFR2 by administering an increased dosage and / or dosing frequency of the antibody or antigen-binding fragment thereof to increase the level of soluble TNFR2; or(b) detecting an increased level of soluble TNFR2 in the subject relative to a reference level of soluble TNFR2, and increasing the dosage and / or dosing frequency of the antibody or antigen-binding fragment thereof.231 . The method of claim 229 or 230, wherein the antibody or antigen-binding fragment thereof is administered to the human subject at a dosing frequency of once every week, once every two weeks, once every three weeks, or once every four weeks.

232. The method of any one of claims 229-231 , wherein the antibody or antigen-binding fragment thereof is administered to the human subject at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg, from about 1 .65 mg / kg to about 2.5 mg / kg, from about 2.2 mg / kg to about 3.0 mg / kg, or from about 2.5 mg / kg to about 4.2 mg / kg.

233. The method of any one of claims 229-232, wherein the antibody or antigen-binding fragment thereof is administered to the human subject:(a) once every week at a dose of from about 0.8 mg / kg to about 1 .2 mg / kg;(b) once every two weeks at a dose of from about 1 .65 mg / kg to about 2.5 mg / kg;(c) once every three weeks at a dose of from about 2.2 mg / kg to about 3.0 mg / kg; or(d) once every four weeks at a dose of from about 2.5 mg / kg to about 4.2 mg / kg.

234. The method of any one of claims 229-233, wherein the method further comprises decreasing the dose range of the antibody or antigen-binding fragment thereof.

235. A modified antibody or antigen-binding fragment thereof that specifically binds tumor necrosis factor receptor 2 (TNFR2), wherein the modified antibody or antigen-binding fragment thereof comprises a heavy chain variable region, a light chain variable region, and a modified human lgG4 constant region comprising a modified human lgG4 Fc hinge region, wherein the modified human lgG4 constant region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1547, wherein the modified human lgG4 Fc hinge region comprises the amino acid substitution of S228P, and wherein the amino acid position is numbered according to the EU index.

236. The modified antibody or antigen-binding fragment thereof of claim 235, wherein the TNFR2 is human TNFR2.

237. The modified antibody or antigen-binding fragment thereof of claim 235, wherein the modified antibody or antigen-binding fragment thereof is a modified human lgG4 antibody or antigenbinding fragment thereof comprising a modified human lgG4 Fc domain comprising the amino acid substitution of S228P.

238. The modified antibody or antigen-binding fragment thereof of claim 237, wherein the modified human lgG4 constant region comprises the amino acid sequence of SEQ ID NO: 1547.

239. The modified antibody or antigen-binding fragment thereof of claim 237 or 238, wherein the heavy chain variable region comprises a heavy chain complementarity determining region 1 (CDR-H1 ), CDR-H2, and CDR-H3, and the light chain variable region comprises a light chain complementarity determining region 1 (CDR-L1 ), CDR-L2, and CDR-L3, wherein the CDR-H1 , CDR- H2, CDR-H3, CDR-L1 , CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs:1413, 1414 or 1420, 1415, 1416, 1417, and 1418, respectively.

240. The modified antibody or antigen-binding fragment thereof of claim 239, wherein the heavy chain variable region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 679, 681 , 1485, 1486, 1487, 1488, 1489, or 1490, and the light chain variable region comprises an amino acid sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 680, 682, 1491 , 1492, 1493, 1494, or 1495.241 . The modified antibody or antigen-binding fragment thereof of claim 239 or 240, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 679,681 , 1485, 1486, 1487, 1488, 1489, or 1490, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 680, 682, 1491 , 1492, 1493, 1494, or 1495.

242. The modified antibody or antigen-binding fragment thereof of claim 241 , wherein:(a) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 679, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 680;(b) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 681 , and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 682; or(c) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1488, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1495.

243. The modified antibody or antigen-binding fragment thereof of any one of claims 237- 242, wherein the modified antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence having at least 95% identity to the sequence of SEQ ID NO:1498, 1499, 1500, 1501 , 1502, or 1503, and a light chain comprising an amino acid sequence having at least 95% identity to the sequence of SEQ ID NO: 1504, 1505, 1506, 1507, or 1508.

244. The modified antibody or antigen-binding fragment thereof of claim 243, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 1498, 1499, 1500, 1501 , 1502, or1503, and the light chain comprises the amino acid sequence of SEQ ID NO: 1504, 1505, 1506, 1507, or 1508.

245. The modified antibody or antigen-binding fragment thereof of claim 239, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1488, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1495, and the modified human lgG4 constant region comprises the amino acid sequence of SEQ ID NO: 1547.

246. The modified antibody or antigen-binding fragment thereof of claim 239, wherein the modified antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1501 and a light chain comprising the amino acid sequence of SEQ ID NO: 1508.

247. The modified antibody or antigen-binding fragment thereof of claim any one of claims 237-246, wherein the modified antibody or antigen-binding fragment thereof is a monoclonal antibody.

248. The modified antibody or antigen-binding fragment thereof of any one of claims 237- 247, wherein the modified antibody or antigen-binding fragment thereof is a humanized antibody.

249. The modified antibody or antigen-binding fragment thereof of any one of claims 235- 248, wherein the modified human lgG4 Fc domain further comprises one or more amino acid modifications selected from the group consisting of:(i) L235E;(ii) D265A;(iii) G237A;(iv) E318A;(v) E233P;(vi) G236R and L328R; and(vii) N297G or N297Q; wherein the amino acid positions are numbered according to the EU index.

250. The modified antibody or antigen-binding fragment thereof of any one of claims 235- 248, wherein the modified human lgG4 Fc domain further comprises one or more amino acid modifications selected from the group consisting of:(i) L235E; and(ii) F234A and L235A; wherein the amino acid positions are numbered according to the EU index.251 . The modified antibody or antigen-binding fragment thereof of any one of claims 237-250, wherein the modified antibody or antigen-binding fragment thereof is an agonistic antibody.

252. The modified antibody or antigen-binding fragment thereof or any one of claims 237-251 , wherein the modified antibody or antigen-binding fragment thereof is formulated for subcutaneous administration.

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