T-Cell Redirecting Bispecific Antibodies for Treatment of Disease

• US 20170022274A1
• Filed: 10/10/2016
• Published: 01/26/2017
• Est. Priority Date: 08/14/2012
• Status: Active Grant

• Current Assignee: IBC Pharmaceuticals Inc.
• Original Assignee: IBC Pharmaceuticals Inc.
• Inventors: Chang, Chien-Hsing, Goldenberg, David M., Rossi, Edmund A., Rossi, Diane
• Granted Patent: US 10,239,938 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/195 Chemokines, e.g. RANTES
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 38/45 Transferases (2)
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/001 by chemical synthesis
• CPC Class Codes: C07K 14/4702 : Regulators; Modulating activity
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2806 : against CD2
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2812 : against CD4
• CPC Class Codes: C07K 16/2815 : against CD8
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/283 : against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/2833 : against MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 16/2842 : against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
• CPC Class Codes: C07K 16/2845 : against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
• CPC Class Codes: C07K 16/2851 : against the lectin superfamily, e.g. CD23, CD72
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/2866 : against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 16/2875 : against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 16/2878 : against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/2884 : against CD44
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/289 : against CD45
• CPC Class Codes: C07K 16/2893 : against CD52
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 16/3007 : Carcino-embryonic Antigens
• CPC Class Codes: C07K 16/3053 : Skin, nerves, brain
• CPC Class Codes: C07K 16/3076 : against structure-related tumour-associated moieties
• CPC Class Codes: C07K 16/3092 : against tumour-associated mucins
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• CPC Class Codes: C07K 16/40 : against enzymes
• CPC Class Codes: C07K 16/44 : against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• CPC Class Codes: C07K 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/35 : Valency
• CPC Class Codes: C07K 2317/53 : Hinge
• CPC Class Codes: C07K 2317/54 : F(ab')2
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C07K 2319/40 : containing a tag for immunodetection, or an epitope for immunisation
• CPC Class Codes: C07K 2319/735 : containing a domain for self-assembly, e.g. a viral coat protein (includes phage display)
• CPC Class Codes: C07K 2319/74 : containing a fusion for binding to a cell surface receptor
• CPC Class Codes: C07K 2319/75 : containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones
• CPC Class Codes: C12N 9/12 : transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Y 207/11001 : Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
• CPC Class Codes: C12Y 207/11011 : cAMP-dependent protein kinase (2.7.11.11)
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention concerns compositions and methods of use of T-cell redirecting complexes, with at least one binding site for a T-cell antigen and at least one binding site for an antigen on a diseased cell or pathogen. Preferably, the complex is a DNL™ complex. More preferably, the complex comprises a bispecific antibody (bsAb). Most preferably, the bsAb is an anti-CD3×anti-CD19 bispecific antibody, although antibodies against other T-cell antigens and/or disease-associated antigens may be used. The complex is capable of targeting effector T cells to induce T-cell-mediated cytotoxicity of cells associated with a disease, such as cancer, autoimmune disease or infectious disease. The cytotoxic immune response is enhanced by co-administration of interferon-based agents that comprise interferon-α, interferon-β, interferon-λ1, interferon-λ2 or interferon-λ3.

Claims

1. A trivalent T-cell redirecting complex comprising a bispecific antibody, wherein the bispecific antibody has two binding sites against a tumor-associated antigen (TAA) and one binding site against a T-cell antigen.

2. The complex of claim 1, wherein the T-cell antigen is selected from the group consisting of CD2, CD3, CD4, CD5, CD6, CD8, CD25, CD28, CD30, CD40, CD40L, CD44, CD45, CD69 and CD90.

3. The complex of claim 2, wherein the T-cell antigen is CD3.

4. The complex of claim 1, wherein the TAA is selected from the group consisting of AFP (alpha fetoprotein), α

4 integrin, carbonic anhydrase IX, complement factor C3, C3a, C3b, C5a, C5, CCL19, CCL21, CD1, CD1a, CD2, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37 CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM-5, CEACAM-6, CSAp, ED-B fibronectin, EGFR, EGP-1 (TROP-2), EGP-2, ErbB2, Factor H, Flt-1, Flt-3, folate receptor, GRO-β

, HLA-DR, HMGB-1, hypoxia inducible factor (HIF), Ia, IFN-α

, IFN-β

, IFN-γ

, IFN-λ

, IGF-1R, IL-2, IL-4R, IL-6R, IL-13R, IL-15R, IL-15, IL-17, IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, insulin-like growth factor-1 (ILGF-1), IP-10, Le(y), MAGE, MCP-1, mCRP, MIP-1A, MIP-1B, MUC1, MUC2, MUC3, MUC4, MUC5ac, NCA-90, NCA-95, PlGF, PSMA, RANTES, T101, TAC, TAG-72, tenascin, Thomson-Friedenreich antigens, Tn antigen, TNF-α

, TRAIL receptor (R1 and R2), tumor necrosis antigen, VEGF, VEGFR and an oncogene product.

5. The complex according to claim 1, wherein the TAA is selected from the group consisting of alpha-fetoprotein (AFP), CD19, CD20, CD22, CD25, CD33, CD52, CD74, CEACAM-5, CEACAM-6, CSAp, EGFR, EpCAM, HER2/neu, HLA-DR, IGF-1R, IL-6R, MUC5ac, PSMA, TNF-α

, TROP-2 and VEGF.

6. The complex according to claim 1, wherein the TAA is selected from the group consisting of CD19, CD20, CD22, HLA-DR or TROP-2.

7. The complex according to claim 1, wherein the complex comprises an anti-TAA antibody or antigen-binding fragment thereof selected from the group consisting of hR1 (anti-IGF-1R), hPAM4 (anti-MUC5ac), hA20 (anti-CD20), hA19 (anti-CD19), hIMMU31 (anti-AFP), hLL1 (anti-CD74), hLL2 (anti-CD22), RFB4 (anti-CD22), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hMN-14 (anti-CEACAM-5), hMN-15 (anti-CEACAM-6), hRS7 (anti-TROP-2), hMN-3 (anti-CEACAM-6), G250 (anti-carbonic anhydrase IX), infliximab (anti-TNF-α

), certolizumab pegol (anti-TNF-α

), adalimumab (anti-TNF-α

), alemtuzumab (anti-CD52), bevacizumab (anti-VEGF), cetuximab (anti-EGFR), gemtuzumab (anti-CD33), ibritumomab (anti-CD20), panitumumab (anti-EGFR), rituximab (anti-CD20), tositumomab (anti-CD20), GA101 (anti-CD20), trastuzumab (anti-HER2/neu), tocilizumab (anti-IL-6 receptor), basiliximab (anti-CD25), daclizumab (anti-CD25), efalizumab (anti-CD11a), and natalizumab (anti-α

4 integrin).

8. The complex according to claim 1, wherein the complex comprises a first antibody moiety and a second antibody moiety.

9. The complex according to claim 8, wherein the first antibody moiety is an IgG antibody and the second antibody moiety is an antigen-binding antibody fragment.

10. The complex of claim 9, wherein the antibody fragment is selected from the group consisting of a F(ab′

)₂, a Fab′

, a F(ab)₂, a Fab, a scFv, and a single domain antibody.

11. The complex of claim 8, wherein the first antibody moiety is conjugated to an AD (anchoring domain) moiety from an AKAP protein and the second antibody moiety is conjugated to a DDD (dimerization and docking domain) moiety from protein kinase A (PKA) regulatory subunit RIα

, RIβ

, RIIα

or RIIβ

, wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form the complex.

12. The complex of claim 11, wherein the amino acid sequence of the DDD moiety is selected from the group consisting of residues 1-44 of RIIα

, 1-44 of RIIβ

, 12-61 of RIα and

13-66 of RIβ

.

13. The complex of claim 11, wherein the amino acid sequence of the AD moiety is selected from the group consisting of SEQ ID NO:

3, SEQ ID NO;

4, SEQ ID NO;

7, SEQ ID NO;

32, SEQ ID NO;

33, SEQ ID NO;

34, SEQ ID NO;

35, SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

38, SEQ ID NO;

39, SEQ ID NO;

40, SEQ ID NO;

41, SEQ ID NO;

42, SEQ ID NO;

43, SEQ ID NO;

44, SEQ ID NO;

45, SEQ ID NO;

46, SEQ ID NO;

47, SEQ ID NO;

48, SEQ ID NO;

49, SEQ ID NO;

50, SEQ ID NO;

51, SEQ ID NO;

52, SEQ ID NO;

53, SEQ ID NO;

54, SEQ ID NO;

55, SEQ ID NO;

56, SEQ ID NO;

57, SEQ ID NO;

58, SEQ ID NO;

59, SEQ ID NO;

60, SEQ ID NO;

61, SEQ ID NO;

62, SEQ ID NO;

63, SEQ ID NO;

64, SEQ ID NO;

65, SEQ ID NO;

66, SEQ ID NO;

67, SEQ ID NO;

68, SEQ ID NO;

69, SEQ ID NO;

70, SEQ ID NO;

71, SEQ ID NO;

72, SEQ ID NO;

73, SEQ ID NO;

74, SEQ ID NO;

75, SEQ ID NO;

76, SEQ ID NO;

77, SEQ ID NO;

78, M SEQ ID NO;

79, SEQ ID NO;

80, SEQ ID NO;

81, SEQ ID NO;

82, SEQ ID NO;

83, SEQ ID NO;

44 and SEQ ID NO;

88.

14. The complex of claim 1, wherein administration of the T-cell redirecting complex to a subject is effective to induce an effector T-cell mediated immune response against cancer cells expressing the TAA.

15. A method of directing effector T cells to a cancer cell in an individual comprising administering to the individual a T-cell redirecting complex of claim 1.

16. A pharmaceutical composition comprising a T-cell redirecting complex of claim 1.

17. A method of treating cancer comprising administering to an individual with cancer a T-cell redirecting complex according to claim 1.

18. The method of claim 17, further comprising administering to the individual an interferon selected from the group consisting of interferon-α

, interferon-β

, interferon-λ

1, interferon-λ

2 and interferon-λ

3.

19. The method of claim 17, further comprising inducing a T-cell mediated cytotoxic immune response against the cancer.

20. The method of claim 18, wherein the combination of interferon and T-cell redirecting complex is more effective than interferon alone and T-cell redirecting complex alone.

21. The method of claim 18, wherein the interferon is administered before, simultaneously with, or after the T-cell redirecting complex.

22. The complex of claim 17, wherein the T-cell antigen is selected from the group consisting of CD2, CD3, CD4, CD5, CD6, CD8, CD25, CD28, CD30, CD40, CD40L, CD44, CD45, CD69 and CD90.

23. The complex of claim 17, wherein the T-cell antigen is CD3.

24. The complex of claim 17, wherein the TAA is selected from the group consisting of AFP (alpha fetoprotein), α

4 integrin, carbonic anhydrase IX, complement factor C3, C3a, C3b, C5a, C5, CCL19, CCL21, CD1, CD1a, CD2, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37 CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM-5, CEACAM-6, CSAp, ED-B fibronectin, EGFR, EGP-1 (TROP-2), EGP-2, ErbB2, Factor H, Flt-1, Flt-3, folate receptor, GRO-β

, HLA-DR, HMGB-1, hypoxia inducible factor (HIF), Ia, IFN-α

, IFN-β

, IFN-γ

, IFN-λ

, IGF-1R, IL-2, IL-4R, IL-6R, IL-13R, IL-15R, IL-15, IL-17, IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, insulin-like growth factor-1 (ILGF-1), IP-10, Le(y), MAGE, MCP-1, mCRP, MIP-1A, MIP-1B, MUC1, MUC2, MUC3, MUC4, MUC5ac, NCA-90, NCA-95, PlGF, PSMA, RANTES, T101, TAC, TAG-72, tenascin, Thomson-Friedenreich antigens, Tn antigen, TNF-α

, TRAIL receptor (R1 and R2), tumor necrosis antigen, VEGF, VEGFR and an oncogene product.

25. The method of claim 17, wherein the TAA is CD19.

26. The method of claim 17, wherein the TAA is TROP-2.

27. The method of claim 17, wherein the TAA is CEACAM-5.

28. The method of claim 17, wherein the cancer is selected from the group consisting of non-Hodgkin'"'"'s lymphoma, B cell lymphoma, B cell leukemia, T cell lymphoma, T cell leukemia, acute lymphoid leukemia, chronic lymphoid leukemia, Burkitt lymphoma, Hodgkin'"'"'s lymphoma, hairy cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, multiple myeloma, glioma, Waldenstrom'"'"'s macroglobulinemia, carcinoma, melanoma, sarcoma, glioma, skin cancer, oral cavity cancer, gastrointestinal tract cancer, colon cancer, stomach cancer, pulmonary tract cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, endometrial cancer, cervical cancer, urinary bladder cancer, pancreatic cancer, bone cancer, liver cancer, gall bladder cancer, kidney cancer, and testicular cancer.

29. The method of claim 17, further comprising administering a therapeutic agent to the subject.

30. The method of claim 29, wherein the therapeutic agent is selected from the group consisting of an antibody, an antibody fragment, a drug, a toxin, an enzyme, a cytotoxic agent, an anti-angiogenic agent, a pro-apoptotic agent, an antibiotics a hormone, an immunomodulator, a cytokine, a chemokine, an antisense oligonucleotide, a small interfering RNA (siRNA), a boron compound and a radioisotope.

31. The method of claim 30, wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3′

,5′

-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839.

32. The method of claim 30, wherein the chemokine is selected from the group consisting of RANTES, MCAF, MIP1-alpha, MIP1-Beta and IP-10.

33. The method of claim 30, wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin and thrombopoietin.

34. The method of claim 30, wherein the cytokine is selected from the group consisting of human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxin, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, tumor necrosis factor-α

, tumor necrosis factor-β

, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, thrombopoietin (TPO), a nerve growth factor (NGF), NGF-β

, platelet-growth factor, a transforming growth factors (TGF), TGF-α

, TGF-β

, insulin-like growth factor-I, insulin-like growth factor-II, erythropoietin (EPO), an osteoinductive factor, an interferon, interferon-α

, interferon-β

, interferon-λ

, a colony stimulating factors (CSF), macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), interleukin-1 (IL-1), IL-1α

, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, LIF, kit-ligand, FLT-3, angiostatin, thrombospondin, endostatin, tumor necrosis factor and LT (lymphotoxin).

35. The method of claim 17, wherein the T-cell redirecting complex is administered intravenously or subcutaneously.