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Last Updated: March 28, 2024

Claims for Patent: 9,352,036


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Summary for Patent: 9,352,036
Title:Delivery system for cytotoxic drugs by bispecific antibody pretargeting
Abstract: The present invention relates to methods and compositions for pretargeting delivery of therapeutic agents. In preferred embodiments, the pretargeting method comprises: a) administering a bispecific antibody with a first binding site for a disease-associated antigen and a hapten on a targetable construct; b) administering a targetable construct comprising at least one therapeutic agent. In preferred embodiments, the bispecific antibody is made by the dock-and-lock (DNL) technique. In a more preferred embodiment, the targetable construct comprises one or more SN-38 moieties.
Inventor(s): McBride; William J. (Boonton, NJ), D\'Souza; Christopher A. (Pomona, NY), Chang; Chien-Hsing (Downingtown, PA), Goldenberg; David M. (Mendham, NJ)
Assignee: Immunomedics, Inc. (Morris Plains, NJ)
Application Number:14/074,447
Patent Claims:1. A method of delivering a therapeutic agent to a human subject comprising: a) administering to the human subject a bispecific antibody construct comprising a first antibody or antigen-binding fragment thereof that binds to a target antigen and a second antibody or antigen-binding fragment thereof that binds to a hapten; and b) administering to the human subject a peptide targetable construct comprising (i) one or more copies of the hapten, (ii) a dendron conjugated to the peptide, and (iii) two or more copies of the therapeutic agent conjugated to the dendron, wherein the first antibody is selected from the group consisting of hR1 (anti-IGF-IR), hPAM4 (anti-mucin), hA20 (anti-CD20), hA19 (anti-CD19), hIMMU31 (anti-AFP), hLL1 (anti-CD74), hLL2 (anti-CD22), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hMN-14 (anti-CEACAM5), hMN-15 (anti-CEACAM6), hRS7 (anti-EGP-1), hMN-3 (anti-CEACAM6), Ab124 (anti-CXCR4) and Ab125 (anti-CXCR4); wherein the hapten is histidine-succinyl-glycine (HSG) or Indium diethylene triamine pentaacetic acid (In-DTPA); and wherein the human subject has cancer expressing the target antigen.

2. The method of claim 1, wherein the target antigen is a tumor-associated antigen (TAA).

3. The method of claim 2, wherein the TAA is selected from the group consisting of CSAp, CD19, IGF-1R, CD20, CD22, CD74, CXCR4, AFP, CEACAM5, CEACAM6, MUC1, EGP-1 and HLA-DR.

4. The method of claim 1, wherein the therapeutic agent is selected from the group consisting of a toxin, drug, radionuclide, immunomodulator, cytokine, lymphokine, chemokine, growth factor, tumor necrosis factor, hormone, hormone antagonist, enzyme, oligonucleotide, siRNA, RNAi, photoactive therapeutic agent, anti-angiogenic agent and pro-apoptotic agent.

5. The method of claim 4, wherein the drug is selected from the group consisting of a nitrogen mustard, ethylenimine derivative, alkyl sulfonate, nitrosourea, triazene, folic acid analog, anthracycline, taxane, COX-2 inhibitor, pyrimidine analog, purine analog, antibiotic, enzyme inhibitor, epipodophyllotoxin, platinum coordination complex, vinca alkaloid, substituted urea, methyl hydrazine derivative, adrenocortical suppressant, hormone antagonist, endostatin, camptothecin, antimetabolite, alkylating agent, antimitotic agent, anti-angiogenic agent, tyrosine kinase inhibitor, mTOR inhibitor, heat shock protein (HSP90) inhibitor, proteosome inhibitor, HDAC inhibitor, and pro-apoptotic agent.

6. The method of claim 4, wherein the drug is selected from the group consisting of 5-fluorouracil, aplidin, azaribine, anastrozole, bendamustine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatinum, irinotecan (CPT-11), SN-38, carboplatin, cladribine, 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 agent, 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, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, and vincristine.

7. The method of claim 4, 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.

8. The method of claim 4, wherein the radionuclide is selected from the group consisting of .sup.103mRh, .sup.103Ru, .sup.105Rh, .sup.105Ru, .sup.107Hg, .sup.109Pd, .sup.109Pt, .sup.111Ag, .sup.111In, .sup.113mIn .sup.119Sb, .sup.11C, .sup.121mTe, .sup.122mTe, .sup.125I, .sup.125mTe, .sup.126I, .sup.131I, .sup.133I, .sup.13N, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.152Dy, .sup.153Sm, .sup.15O, .sup.161Ho, .sup.161Tb, .sup.165Tm, .sup.166Dy, .sup.166Ho, .sup.167Tm, .sup.168Tm, .sup.169Er, .sup.169Yb, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189mOs, .sup.189Re, .sup.192Ir, .sup.194Ir, .sup.197Pt, .sup.198Au, .sup.199Au, .sup.201Tl, .sup.203Hg, .sup.211At, .sup.211Bi, .sup.211Pb, .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.215Po, .sup.217At, .sup.219Rn, .sup.221Fr, .sup.223Ra, .sup.224Ac, .sup.225Ac, .sup.225Fm, .sup.32P, .sup.33P, .sup.47Sc, .sup.51Cr, .sup.57Co, .sup.58Co, .sup.59Fe, .sup.62Cu, .sup.67Cu, .sup.67Ga, .sup.75Br, .sup.75Se, .sup.76Br, .sup.77As, .sup.77Br, .sup.80mBr, .sup.89Sr, .sup.90Y, .sup.95Ru, .sup.97Ru, .sup.99Mo and .sup.99mTc.

9. The method of claim 4, wherein the radionuclide is an alpha-particle-emitting radionuclide.

10. The method of claim 4, wherein the enzyme is selected from the group consisting of malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase.

11. The method of claim 1, wherein the second antibody is an anti-HSG or anti-In-DTPA antibody.

12. The method of claim 1, wherein the target antigen is a human target antigen.

13. The method of claim 1, wherein the bispecific antibody construct is TF2 comprising two CEACAM5-binding hMN-14 Fab moieties and one HSG-binding h679 Fab moiety or TF10 comprising two humanized anti-pancreatic cancer mucin MAb-binding hPAM4 Fab moieties and one HSG-binding h679 Fab moiety.

14. The method of claim 1, wherein the therapeutic agent is SN-38.

15. The method of claim 1, wherein four copies of the therapeutic agent are attached to the targetable construct.

16. The method of claim 1, wherein 8 to 16 copies of the therapeutic agent are attached to the targetable construct.

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