Multi-specific binding conjugate, related pharmaceutical compositions and use

Abstract

The present invention relates to a multi-specific binding conjugate, a related composition and use. The binding conjugate comprises binding moieties for two or more different receptors, co-receptors, antigens or cellular markers which moieties are coupled by a nanomaterial. The multi-specific binding conjugate can be used to modulate an immune response, treat or prevent a disease or condition (e.g., a cancer, autoimmune disease, pathogen infection or inflammatory disease).

1 . A multispecific binding conjugate comprising:
 a) at least one first binding moiety that binds to a receptor, co-receptor, antigen and/or cellular marker on a cytotoxic effector cell which is a leukocyte which is selected from the group consisting of an NK cell and an NKT cell; and   b) at least one second binding moiety that binds to a receptor, co-receptor, antigen and/or cellular marker on a target cell which is a tumor cell; wherein the first binding moiety is an antibody or a fragment thereof;   wherein the first binding moiety and the second binding moiety are coupled to a nanoparticle which is preferably a biodegradable nanomaterial, more preferably any one of or a mixture of at least two of polylactic acid-co-glycolic acid), polylactic acid, polycaprolactone, polybutylene succinate, polyaniline, polycarbonate, poly(glycolide-co-lactide) or poly(glycolide-co-caprolactone).   
     
     
         2 . The conjugate according to  claim 1  wherein the receptor, co-receptor, antigen and/or cellular marker on the NK cell is selected from the group consisting of CD16, CD56, CD57, ADAM17 and CD137; and
 b) the target cell is a diseased cell or pathogen. 
 
     
     
         3 . The conjugate according to  claim 2 , wherein the receptor, co-receptor, antigen and/or cell marker on the diseased cell is selected from the group consisting of: carbonic anhydrase IX, alpha-fetoprotein, alpha-actinin-4, A3, A33 antibody-specific antigen, AFP, ART-4, B7, Ba 733, BAGE, BrE3-antigen, CA125, CAMEL, CAP-1, CASP-8/m, CCCL19, CCCL21, CD1, CD1a, CD2, CD3, 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, CD70L, CD74, CD79a, CD79b, CD80, CD83, CD95, CD126, CD132, CD133, CD138, CD147, CD154, CDC27, CDK-4/m, CDKN2A, CXCR4, CXCR7, CXCL12, HIF-1alpha, colon-specific antigen-p (CSAp), CEA(CEACAM5), CEACAM6, c-met, DAM, EGFR, EGFRvIII, EGP-1, EGP-2, ELF2-M, Ep-CAM, Fit-1, Flt-3, folate receptor, G250 antigen, GAGE, gp100, GROB, HLA-DR, HM1.24, human chorionic gonadotropin (HCG) and its subunit, HER2/neu, HMGB-1, hypoxia-inducible factor (HIF-1), HSP70-2M, HST-2, Ia, IGF-1R, IFN-γ, IFN-α, IFN-β, IL-2, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-23, IL-25, insulin-like growth factor-1 (IGF-1), KC4-antigen, KS-1-antigen, KS1-4, Le-Y, LDR/FUT, macrophage migration inhibitory factor (MIF), MAGE, MAGE-3, MART-1, MART-2, NY-ESO-1, TRAG-3, mCRP, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5ac, MUC13, MUC16, MUM-1/2, MUM-3, NCA66, NCA95, NCA90, pancreatic cancer mucin, placental growth factor, p53, PLAGL2, prostate acid phosphatase, PSA, PRAME, PSMA, PIGF, ILGF, ILGF-1R, IL-6, IL-25, RS5, RANTES, T101, SAGE, S100, survivin, survivin-2B, TAC, TAG-72, tenascin, TRAIL receptor, TNF-alpha, Tn antigen, Thomson-Friedrich antigen, tumor necrosis antigen, TROP-2, VEGFR, ED-B fibronectin, WT-1, 17-1A-antigen, complement factor C3, C3a, C3b, C5a, C5, angiogenesis marker, bc1-2, bc1-6, Kras, cMET, oncogene product. 
     
     
         4 . The conjugate according to  claim 2 , wherein the receptor, co-receptor, antigen and/or cell marker on the diseased cell is a cell surface protein selected from the group consisting of cholecystokinin B Receptor, gonadotropin releasing hormone receptor, somatostatin receptor 2, avb3 integrin, gastrin releasing peptide receptor, neurokinin 1 receptor, melanocortin 1 receptor, neurotensin receptor, neuropeptide Y receptor and C-type lectin-like molecule 1. 
     
     
         5 . The conjugate according to  claim 1 , wherein the first binding moiety binds to CD16 or CD56. 
     
     
         6 . (canceled) 
     
     
         7 . The conjugate according to  claim 1 , wherein the second binding moiety binds to an antigen selected from the group consisting of AFP, CD19, CD20, CD38, MUC1, EGFR and HER2/neu. 
     
     
         8 . The conjugate according to  claim 1 , wherein the antibody is selected from the group consisting of hR1 (anti-IGF-1R), hPAM4 (anti-mucin), KC4 (anti-mucin), 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-CEACAM5), hMN-15 (anti-CEACAM6), hRS7 (anti-TROP-2), hMN-3 (anti-CEACAM6), CC49 (anti-TAG-72), J591 (anti-PSMA), D2/B (anti-PSMA), 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-CD1Ia), muromonab-CD3 (anti-CD3 receptor), natalizumab (anti-α4 integrin), BWA-3 (anti-histone H2A/H4), LG2-1 (anti-histone H3), MRA12 (anti-histone H1), PR1-1 (anti-histone H2B), LG11-2 (anti-histone H2B), LG2-2 (anti-histone H2B), P4/D10 (anti-gp120) and omalizumab (anti-IgE). 
     
     
         9 . The conjugate according to  claim 1 , wherein the second antibody is selected from the group consisting of hA19, hR1, hPAM4, hA20 (veltuzumab), hIMMU31, hLL1 (milatuzumab), hLL2 (epratuzumab), hMu-9, hL243, hMN-14, hMN-15, hRS7 and hMN-3. 
     
     
         10 . The conjugate according to  claim 1 , wherein the nanoparticle is poly(lactic acid-co-glycolic acid), polylactic acid and/or polycaprolactone. 
     
     
         11 . The conjugate according to  claim 1 , wherein the conjugate further comprises the first binding moiety that binds to the receptor, co-receptor, antigen and/or cellular marker on the T cell. 
     
     
         12 . The conjugate according to  claim 11 , wherein the receptor, co-receptor, antigen and/or cellular marker on the T cell is selected from the group consisting of CD2, CD3, CD4, CD5, CD6, CD8, CD25, CD28, CD30, CD40, CD40L, CD44, CD45, CD69 and CD90. 
     
     
         13 . A pharmaceutical composition comprising the conjugate of  claim 1 . 
     
     
         14 . The pharmaceutical composition according to  claim 13  further comprising leukocyte, the leukocyte comprising NK cell. 
     
     
         15 . The pharmaceutical composition according to  claim 13 , further comprising an additional therapeutic agent, preferably selected from the group consisting of an antibody, an antibody fragment, a drug, a toxin, an enzyme, a cytotoxic agent, an anti-angiogenic agent, pro-apoptotic agent, antibiotic, hormone, immunomodulator, cytokine, chemokine, antisense oligonucleotide, small interfering RNA (siRNA), boron compound, and radioisotope. 
     
     
         16 . A method of treating a disease or condition in a subject in need thereof, comprising administering to the subject the multispecific binding conjugate of  claim 1 . 
     
     
         17 . The method according to  claim 16 , wherein the disease or condition is cancer, preferably a cancer selected from the group consisting of non-Hodgkin's lymphoma, B cell lymphoma, B cell leukemia, T cell lymphoma, T cell leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Burkitt's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, multiple myeloma, glioma, Waldenstrom's macroglobulinemia, carcinoma, melanoma, sarcoma, glioma, skin cancer, oral cancer, gastrointestinal cancer, colon cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, pancreatic cancer, bone cancer, liver cancer, gallbladder cancer, kidney cancer, testicular cancer, epithelial cancer, colorectal cancer, stomach cancer, brain cancer, glioblastoma, pancreatic cancer, myeloid leukemia, cervical cancer, medullary thyroid carcinoma, astrocytoma, prostate cancer, bladder cancer, neuroendocrine cancer, gastrointestinal pancreatic tumor, exocrine pancreatic cancer and Ewing sarcoma. 
     
     
         18 . The method according to  claim 16 , further comprising administering to the subject an additional therapeutic agent, preferably selected from the group consisting of an antibody, an antibody fragment, a drug, a toxin, an enzyme, a cytotoxic agent, an anti-angiogenic agent, pro-apoptotic agent, antibiotic, hormone, immunomodulator, cytokine, chemokine, antisense oligonucleotide, small interfering RNA (siRNA), boron compound, and radioisotope.