Tumor therapy by bispecific antibody pretargeting

Patent metadata

Field	Value
Publication number	US-2016287732-A1
Application number	US-201514942315-A
Country	US
Kind code	A1
Filing date	Nov 16, 2015
Priority date	Jan 9, 2015
Publication date	Oct 6, 2016
Grant date	—

Abstract

The present invention relates to methods and compositions for pretargeting delivery of alpha-emitting radionuclides, such as 213 Bi or 225 AC to a target cell or tissue, such as a cancer cell or a tumor. In preferred embodiments, the pretargeting method comprises: a) administering a bispecific antibody comprising at least one binding site for a tumor-associated antigen (TAA) and at least one binding site for a hapten; and b) administering a hapten-conjugated targetable construct that is labeled with an alpha-emitting radionuclide. More preferably, the bispecific antibody is rapidly internalized into the target cell, along with the radionuclide. In most preferred embodiments, the bispecific antibody is made as a dock-and-lock (DNL) complex.

First claim

What is claimed is:

1 . A method of delivering an alpha-particle emitting radionuclide to a tumor comprising:
a) administering to a subject with a tumor a bispecific antibody having one binding site for a tumor-associated antigen (TAA) and one binding site for a hapten; and b) administering to the subject a hapten-containing targetable construct labeled with an alpha-particle emitting radionuclide.

2 . The method of claim 1 , wherein the bispecific antibody is internalized into tumor cells.

3 . The method of claim 1 , wherein the subject is a human subject.

4 . The method of claim 1 , wherein the bispecific antibody is a complex comprising a first fusion protein and a second fusion protein, wherein the first fusion protein comprises an first antibody or antigen-binding antibody fragment attached to a dimerization and docking domain (DDD) moiety from human protein kinase A regulatory subunit RI, RI, RII or RII, and the second fusion protein comprises a second antibody or antigen-binding antibody fragment attached to an anchoring domain (AD) moiety from a human A-kinase anchoring protein (AKAP).

5 . The method of claim 4 , wherein the bispecific antibody is TF12.

6 . The method of claim 1 , wherein the radionuclide is selected from the group consisting of Dy-152, At-211, Bi-212, Ra-223, Rn-219, Po-215, Bi-211, Ac-225, Fr-221, At-217, Bi-213, Fm-255 and Th-227.

7 . The method of claim 1 , wherein the radionuclide is Bi-213 or Ac-225.

8 . The method of claim 1 , wherein the targetable construct is selected from the group consisting of IMP288, IMP402, IMP453, IMP457 and IMP498.

9 . The method of claim 1 , wherein the bispecific antibody comprises an anti-TAA antibody or antigen binding fragment thereof selected from the group consisting of hRS7, hLL1, hLL2, hR1, hPAM4, hA20, hA19, hIMMU31, hMu-9, hL243, hMN-14, hMN-15, hMN-3, RFB4, rituximab, obinutuxumab, lambrolizumab, nivolumab, ipilimumab, pidilizumab, tremelimumab, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, KC4, TAG-72, J591, AB-PG1-XG1-026, D2/B, G250, alemtuzumab, bevacizumab, cetuximab, gemtuzumab, ibritumomab tiuxetan, panitumumab, tositumomab, and trastuzumab.

10 . The method of claim 1 , wherein the hapten is HSG or In-DTPA.

11 . The method of claim 10 , wherein the bispecific antibody comprises an anti-hapten antibody or antigen-binding fragment thereof selected from the group consisting of h679 and h734.

12 . The method of claim 1 , further comprising administering to the subject a therapeutic agent selected from the group consisting of toxins, drugs, radionuclides, immunomodulators, cytokines, lymphokines, chemokines, growth factors, tumor necrosis factors, hormones, hormone antagonists, enzymes, oligonucleotides, siRNA, RNAi, photoactive therapeutic agents, anti-angiogenic agents and pro-apoptotic agents.

13 . The method of claim 12 , wherein the drug is selected from the group consisting of 5-fluorouracil, aplidin, azaribine, anastrozole, anthracyclines, bendamustine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), pro-2P-DOX, cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, estramustine, epipodophyllotoxin, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, gemcitabine, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, lenolidamide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, nitrosourea, plicomycin, procarbazine, paclitaxel, pentostatin, PSI-341, raloxifene, semustine, streptozocin, tamoxifen, taxol, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine and vinca alkaloids.

14 . The method of claim 13 , wherein the therapeutic agent is SN-38 or pro-2P-DOX.

15 . The method of claim 12 , wherein the toxin is selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.

16 . The method of claim 12 , wherein the radionuclide is selected from the group consisting of 103m Rh, 103 Ru, 105 Rh, 105 Ru, 107 Hg, 109 Pd, 109 Pt, 111 Ag, 111 In, 113m In, 119 Sb, 11 C, 121m Te, 122m Te, 125 I, 125m Te, 126 I, 131 I, 133 I, 13 N, 142 Pr, 143 Pr, 149 Pm, 152 Dy, 153 Sm, 15 O, 161 Ho, 161 Tb, 165 Tm, 166 Dy, 166 Ho, 167 Tm, 168 Tm, 169 Er, 169 Yb, 177 Lu, 186 Re, 188 Re, 189m Os, 189 Re, 192 Ir, 194 Ir, 197 Pt, 198 Au, 199 Au, 201 Tl, 203 Hg, 211 At, 211 Bi, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 215 Po, 217 At, 219 Rn, 221 Fr, 223 Ra, 224 Ac, 225 Ac, 225 Fm, 32 P, 33 P, 47 c, 51 Cr, 57 Co, 58 Co, 59 Fe, 62 Cu, 67 Cu, 67 Ga, 75 Br, 75 Se, 76 Br, 77 As, 77 Br, 80m Br, 89 Sr, 90 Y, 95 Ru, 97 Ru, 99 Mo, 99m Tc and 227 Th.

17 . The method of claim 12 , 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.

18 . The method of claim 17 , wherein the cytokine is selected from the group consisting of human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, 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, NGF-β, platelet-growth factor, TGF-α, TGF-β, insulin-like growth factor-I, insulin-like growth factor-II, interferon-α, interferon-β, interferon-γ, interferon-λ, macrophage-CSF, 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, IL-25, LIF, kit-ligand, angiostatin, thrombospondin, endostatin, tumor necrosis factor and lymphotoxin.

19 . The method of claim 1 , wherein the TAA is selected from the group consisting of carbonic anhydrase IX, CCL19, CCL21, CSAp, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, IGF-1R, 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, CXCR4, CXCR7, CXCL12, HIF-1α, AFP, PSMA, CEACAM5, CEACAM6, c-met, B7, ED-B of fibronectin, Factor H, FHL-1, Flt-3, folate receptor, GROB, HMGB-1, hypoxia inducible factor (HIF), HM1.24, insulin-like growth factor-1 (ILGF-1), 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-25, IP-10, MAGE, mCRP,

Assignees

• Immunomedics Inc

Inventors

• Boerman Otto C
• Heskamp Sandra
• Chang Chien-Hsing
• Mcbride William J
• Goldenberg David M

Classifications

• A61K47/6879

  the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin · CPC title

• A61K47/595

  Polyamides, e.g. nylon (polyamino acids A61K47/62) · CPC title

• C07K16/44

  against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids} · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07K16/30

  from tumour cells · CPC title