ANTI-TUMOR NECROSIS FACTOR RECEPTOR (TNFR2) ANTIBODIES AND USES THEREOF

1 . An isolated anti-TNFR2 (tumor necrosis factor receptor 2) antibody comprising a set of three complementarity determining regions (CDRs) on a heavy chain (HCDR1, HCDR2, and HCDR3) and a set of three CDRs on a light chain (LCDR1, LCDR2, and LCDR3), wherein said VH comprises heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2 and HCDR3, said VL comprises light chain complementarity determining regions (LCDRs) LCDR1, LCDR2 and LCDR3, wherein said CDRs have the amino acid sequences of

(a) SEQ ID NO: 187, SEQ ID NO:345, and SEQ ID NO: 356 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 377, and SEQ ID NO: 395 (LCDR1, LCDR2, and LCDR3, respectively);

(b) SEQ ID NO: 402, SEQ ID NO:345, and SEQ ID NO: 413 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 418, and SEQ ID NO: 427 (LCDR1, LCDR2, and LCDR3, respectively);

(c) SEQ ID NO: 398, SEQ ID NO:346, and SEQ ID NO: 407 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 377, and SEQ ID NO: 419 (LCDR1, LCDR2, and LCDR3, respectively);

(d) SEQ ID NO: 187, SEQ ID NO:346, and SEQ ID NO: 408 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 377, and SEQ ID NO: 420 (LCDR1, LCDR2, and LCDR3, respectively);

(e) SEQ ID NO: 189, SEQ ID NO:406, and SEQ ID NO: 409 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 377, and SEQ ID NO: 421 (LCDR1, LCDR2, and LCDR3, respectively);

(f) SEQ ID NO: 187, SEQ ID NO:345, and SEQ ID NO: 410 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 418, and SEQ ID NO: 422 (LCDR1, LCDR2, and LCDR3, respectively);

(g) SEQ ID NO: 399, SEQ ID NO:346, and SEQ ID NO: 411 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 418, and SEQ ID NO: 423 (LCDR1, LCDR2, and LCDR3, respectively);

(h) SEQ ID NO: 400, SEQ ID NO:346, and SEQ ID NO: 412 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 417, SEQ ID NO: 377, and SEQ ID NO: 424 (LCDR1, LCDR2, and LCDR3, respectively);

(i) SEQ ID NO: 401, SEQ ID NO:346, and SEQ ID NO: 413 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 417, SEQ ID NO: 418, and SEQ ID NO: 425 (LCDR1, LCDR2, and LCDR3, respectively);

(j) SEQ ID NO: 401, SEQ ID NO:346, and SEQ ID NO: 414 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 417, SEQ ID NO: 418, and SEQ ID NO: 426 (LCDR1, LCDR2, and LCDR3, respectively);

(k) SEQ ID NO: 398, SEQ ID NO:346, and SEQ ID NO: 415 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 417, SEQ ID NO: 377, and SEQ ID NO: 428 (LCDR1, LCDR2, and LCDR3, respectively);

(l) SEQ ID NO: 403, SEQ ID NO:346, and SEQ ID NO: 412 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 418, and SEQ ID NO: 429 (LCDR1, LCDR2, and LCDR3, respectively);

(m) SEQ ID NO: 404, SEQ ID NO:346, and SEQ ID NO: 412 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 418, and SEQ ID NO: 425 (LCDR1, LCDR2, and LCDR3, respectively);

(n) SEQ ID NO: 401, SEQ ID NO:346, and SEQ ID NO: 414 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 417, SEQ ID NO: 418, and SEQ ID NO: 430 (LCDR1, LCDR2, and LCDR3, respectively);

(o) SEQ ID NO: 405, SEQ ID NO:406, and SEQ ID NO: 416 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 377, and SEQ ID NO: 431 (LCDR1, LCDR2, and LCDR3, respectively);

(p) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 378 (LCDR1, LCDR2, and LCDR3, respectively);

(q) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 378 (LCDR1, LCDR2, and LCDR3, respectively);

(r) SEQ ID NO: 185, SEQ ID NO:334, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 360, SEQ ID NO: 372, and SEQ ID NO: 379 (LCDR1, LCDR2, and LCDR3, respectively);

(s) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 380 (LCDR1, LCDR2, and LCDR3, respectively);

(t) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 381 (LCDR1, LCDR2, and LCDR3, respectively);

(u) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 361, SEQ ID NO: 372, and SEQ ID NO: 381 (LCDR1, LCDR2, and LCDR3, respectively);

(v) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 362, SEQ ID NO: 372, and SEQ ID NO: 382 (LCDR1, LCDR2, and LCDR3, respectively);

(w) SEQ ID NO: 185, SEQ ID NO:335, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 363, SEQ ID NO: 372, and SEQ ID NO: 383 (LCDR1, LCDR2, and LCDR3, respectively);

(x) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 364, SEQ ID NO: 372, and SEQ ID NO: 384 (LCDR1, LCDR2, and LCDR3, respectively);

(y) SEQ ID NO: 185, SEQ ID NO:336, and SEQ ID NO: 348 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 365, SEQ ID NO: 372, and SEQ ID NO: 378 (LCDR1, LCDR2, and LCDR3, respectively);

(z) SEQ ID NO: 185, SEQ ID NO:337, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 373, and SEQ ID NO: 385 (LCDR1, LCDR2, and LCDR3, respectively);

(aa) SEQ ID NO: 185, SEQ ID NO:338, and SEQ ID NO: 348 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 386 (LCDR1, LCDR2, and LCDR3, respectively);

(bb) SEQ ID NO: 185, SEQ ID NO:339, and SEQ ID NO: 349 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 378 (LCDR1, LCDR2, and LCDR3, respectively);

(cc) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 350 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 366, SEQ ID NO: 372, and SEQ ID NO: 387 (LCDR1, LCDR2, and LCDR3, respectively);

(dd) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 351 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 378 (LCDR1, LCDR2, and LCDR3, respectively);

(ee) SEQ ID NO: 185, SEQ ID NO:334, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 360, SEQ ID NO: 372, and SEQ ID NO: 388 (LCDR1, LCDR2, and LCDR3, respectively);

(ff) SEQ ID NO: 185, SEQ ID NO:334, and SEQ ID NO: 352 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 378 (LCDR1, LCDR2, and LCDR3, respectively);

(gg) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 352 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 389 (LCDR1, LCDR2, and LCDR3, respectively);

(hh) SEQ ID NO: 185, SEQ ID NO:334, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 359, SEQ ID NO: 372, and SEQ ID NO: 378 (LCDR1, LCDR2, and LCDR3, respectively);

(ii) SEQ ID NO: 185, SEQ ID NO:190, and SEQ ID NO: 347 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 365, SEQ ID NO: 372, and SEQ ID NO: 378 (LCDR1, LCDR2, and LCDR3, respectively);

(jj) SEQ ID NO: 185, SEQ ID NO:336, and SEQ ID NO: 352 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 365, SEQ ID NO: 372, and SEQ ID NO: 390 (LCDR1, LCDR2, and LCDR3, respectively);

(kk) SEQ ID NO: 185, SEQ ID NO:336, and SEQ ID NO: 352 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 365, SEQ ID NO: 374, and SEQ ID NO: 391 (LCDR1, LCDR2, and LCDR3, respectively);

(ll) SEQ ID NO: 186, SEQ ID NO:340, and SEQ ID NO: 353 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 375, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(mm) SEQ ID NO: 186, SEQ ID NO:341, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 375, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(nn) SEQ ID NO: 186, SEQ ID NO:341, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 368, SEQ ID NO: 375, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(oo) SEQ ID NO: 186, SEQ ID NO:342, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 375, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(pp) SEQ ID NO: 186, SEQ ID NO:343, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 369, SEQ ID NO: 375, and SEQ ID NO: 393 (LCDR1, LCDR2, and LCDR3, respectively);

(qq) SEQ ID NO: 186, SEQ ID NO:343, and SEQ ID NO: 355 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 375, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(rr) SEQ ID NO: 186, SEQ ID NO:341, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 375, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(ss) SEQ ID NO: 186, SEQ ID NO:341, and SEQ ID NO: 355 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 376, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(tt) SEQ ID NO: 186, SEQ ID NO:344, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 370, SEQ ID NO: 375, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(uu) SEQ ID NO: 186, SEQ ID NO:341, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 375, and SEQ ID NO: 394 (LCDR1, LCDR2, and LCDR3, respectively);

(vv) SEQ ID NO: 186, SEQ ID NO:344, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 375, and SEQ ID NO: 392 (LCDR1, LCDR2, and LCDR3, respectively);

(ww) SEQ ID NO: 186, SEQ ID NO:341, and SEQ ID NO: 354 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 367, SEQ ID NO: 375, and SEQ ID NO: 393 (LCDR1, LCDR2, and LCDR3, respectively);

(xx) SEQ ID NO: 188, SEQ ID NO:345, and SEQ ID NO: 357 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 377, and SEQ ID NO: 396 (LCDR1, LCDR2, and LCDR3, respectively);

(yy) SEQ ID NO: 189, SEQ ID NO:346, and SEQ ID NO: 358 (HCDR1, HCDR2, and HCDR3, respectively), and SEQ ID NO: 371, SEQ ID NO: 377, and SEQ ID NO: 397 (LCDR1, LCDR2, and LCDR3, respectively).

2 . The anti-TNFR2 antibody of claim 1 , wherein the antibody comprises a heavy chain variable region and a light chain variable region, said heavy chain variable region and light chain variable region comprise the amino acid sequences selected from the group consisting of SEQ ID NOs:87-88, SEQ ID NOs:289-290, SEQ ID NOs:3-4, SEQ ID NOs:7-8, SEQ ID NOs:11-12, SEQ ID NOs:15-16, SEQ ID NOs:19-20, SEQ ID NOs:23-24, SEQ ID NOs:27-28, SEQ ID NOs:31-32, SEQ ID NOs:35-36, SEQ ID NOs:39-40, SEQ ID NOs:43-44, SEQ ID NOs:47-48, SEQ ID NOs:51-52, SEQ ID NOs:55-56, SEQ ID NOs:59-60, SEQ ID NOs:63-64, SEQ ID NOs:67-68, SEQ ID NOs:71-72, SEQ ID NOs:75-76, SEQ ID NOs:79-80, SEQ ID NOs:83-84, SEQ ID NOs:91-92, SEQ ID NOs:95-96, SEQ ID NOs:99-100, SEQ ID NOs:103-104, SEQ ID NOs:107-108, SEQ ID NOs:111-112, SEQ ID NOs:115-116, SEQ ID NOs:119-120, SEQ ID NOs:123-124, SEQ ID NOs:127-128, SEQ ID NOs:131-132, SEQ ID NOs:135-136, SEQ ID NOs:139-140, SEQ ID NOs:143-144, SEQ ID NOs:147-148, SEQ ID NOs:151-152, SEQ ID NOs:157-158, SEQ ID NOs:163-164, SEQ ID NOs:169-170, SEQ ID NOs:175-176, SEQ ID NOs:181-182, SEQ ID NOs:193-194, SEQ ID NOs:199-200, SEQ ID NOs:205-206, SEQ ID NOs:211-212, SEQ ID NOs:217-218, SEQ ID NOs:223-224, SEQ ID NOs:229-230, SEQ ID NOs:233-234, SEQ ID NOs:237-238, SEQ ID NOs:241-242, SEQ ID NOs:245-246, SEQ ID NOs:249-250, SEQ ID NOs:253-254, SEQ ID NOs:261-262, SEQ ID NOs:265-266, SEQ ID NOs:269-270, SEQ ID NOs:273-274, SEQ ID NOs:277-278, SEQ ID NOs:281-282, SEQ ID NOs:285-286, SEQ ID NOs:293-294, SEQ ID NOs:297-298, SEQ ID NOs:301-302, SEQ ID NOs:305-306, SEQ ID NOs:309-310, SEQ ID NOs:313-314, SEQ ID NOs:317-318, SEQ ID NOs:321-322, SEQ ID NOs:325-326, and SEQ ID NOs:329-330.

3 . The anti-TNFR2 antibody of claim 1 , wherein the antibody comprises a heavy chain and a light chain, said heavy chain and a light chain comprise the amino acid sequences selected from the group consisting of SEQ ID NOs 432 and 260, SEQ ID NOs: 438 and 292, SEQ ID NOs: 291-292, SEQ ID NOs:235-236, SEQ ID NOs:239-240, SEQ ID NOs:243-244, SEQ ID NOs:247-248, SEQ ID NOs:251-252, SEQ ID NOs:255-256, SEQ ID NOs:259-260, SEQ ID NOs:263-264, SEQ ID NOs:267-268, SEQ ID NOs:271-272, SEQ ID NOs:275-276, SEQ ID NOs:279-280, SEQ ID NOs:283-284, SEQ ID NOs:287-288, SEQ ID NOs:295-296, SEQ ID NOs:299-300, SEQ ID NOs:303-304, SEQ ID NOs:307-308, SEQ ID NOs:311-312, SEQ ID NOs:315-316, SEQ ID NOs:319-320, SEQ ID NOs:323-324, SEQ ID NOs:327-328, SEQ ID NOs:331-332, SEQ ID NOs: 433 and 304, SEQ ID NOs: 434 and 308, SEQ ID NOs: 434 and 308, SEQ ID NOs: 435 and 236, SEQ ID NOs: 436 and 244, SEQ ID NOs: 437 and 284, and SEQ ID NOs: 439 and 296.

4 . The anti-TNFR2 antibody of claim 1 , wherein the antibody is an IgG, a Fv, a scFv, a Fab, a F(ab′) 2 , a minibody, a diabody, a triabody, a nanobody, a bispecific antibody, or a single domain antibody.

5 . The anti-TNFR2 antibody of claim 4 , wherein said IgG is IgG1, IgG2, IgG3, or IgG4.

6 . The anti-TNFR2 antibody of claim 1 , wherein the antibody agonizes TNFR2.

7 . The anti-TNFR2 antibody of claim 6 , wherein the antibody agonizes TNFR2 in an Fc independent manner.

8 . The anti-TNFR2 antibody of claim 1 , wherein the antibody has an EC 50 binding measurement of about 0.05-100 nM.

9 . The anti-TNFR2 antibody of claim 1 , wherein the antibody has an EC 50 functional agonism measurement of about 0.05-100 nM.

10 . The anti-TNFR2 antibody of claim 1 , wherein the antibody activates signaling through TNFR2 at a level of at least 80% as compared to signaling activated by TNF.

11 . The anti-TNFR2 antibody of claim 1 , wherein the antibody activates signaling through TNFR2 at a level of at least 95% as compared to signaling activated by TNF.

12 . A composition comprising the anti-TNFR2 antibody of claim 1 and a pharmaceutically acceptable carrier.

13 . An isolated polynucleotide sequence encoding the anti-TNFR2 antibody of claim 1 .

14 . A vector comprising the polynucleotide sequence of claim 13 .

15 . A host cell comprising the vector of claim 14 .

16 . A method of modulating activities or functions of regulatory T cells in a subject, comprising the step of administering to the subject a composition comprising an effective amount of the anti-TNFR2 antibody of claim 1 .

17 . The method of claim 16 , wherein the regulatory T cells are CD4 + CD25 + Foxp3 + .

18 . The method of claim 16 , wherein the method stimulates proliferation of the regulatory T cells.

19 . The method of claim 16 , wherein the method activates said regulatory T cells.

20 . The method of claim 16 , wherein the method modulates immune responses mediated by said regulatory T cells.

21 . A method of modulating activities or functions of myeloid-derived suppressor cells (MDSCs) in a subject, comprising the step of administering to the subject a composition comprising an effective amount of the anti-TNFR2 antibody of claim 1 .

22 . The method of claim 21 , wherein the method stimulates proliferation of the MDSCs.

23 . The method of claim 21 , wherein the method activates said MDSCs.

24 . A method of treating a disease in a subject, comprising the step of administering to the subject a composition comprising an effective amount of the anti-TNFR2 antibody of claim 1 .

25 . The method of claim 24 , wherein the disease is a cancer, an autoimmune disease, GvHD, a viral infection, or a bacterial infection.