Claims for Patent: 8,758,726

Summary for Patent: 8,758,726

Title:	Methods and compositions for improved F-18 labeling of proteins, peptides and other molecules
Abstract:	The present application discloses compositions and methods of synthesis and use of .sup.18F or .sup.19F-labeled molecules of use in PET, SPECT and/or MR imaging. Preferably, the .sup.18F or .sup.19F is conjugated to a targeting molecule by formation of a complex with a group IIIA metal and binding of the complex to a bifunctional chelating agent, which may be directly or indirectly attached to the targeting molecule. In other embodiments, the .sup.18F or .sup.19F labeled moiety may comprise a targetable construct used in combination with a bispecific antibody to target a disease-associated antigen. The disclosed methods and compositions allow the simple and reproducible labeling of molecules at very high efficiency and specific activity in 30 minutes or less. In preferred embodiments, the labeled molecule may be used for imaging in a subject without purification after labeling.
Inventor(s):	D\'Souza; Christopher A. (Pomona, NY), McBride; William J. (Boonton, NJ), Goldenberg; David M. (Mendham, NJ)
Assignee:	Immunomedics, Inc. (Morris Plains, NJ)
Application Number:	14/012,582
Patent Claims:	1. A method of imaging by positron emission tomography (PET) or magnetic resonance imaging (MRI) comprising: a) obtaining an .sup.19F- or .sup.18F-labeled targeting molecule comprising a bifunctional chelating agent of the structure ##STR00026## wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of ##STR00027## and R.sub.3 is selected from the group consisting of: ##STR00028## ##STR00029## wherein M selected from the group consisting of aluminum, gallium, indium, lutetium and thallium and X is .sup.19F or .sup.18F, wherein n=1-9 and wherein R=F, CH.sub.2F, CHF.sub.2, CH.sub.3 or OCF.sub.3; b) administering the .sup.19F- or .sup.18F-labeled targeting molecule to a subject; and c) imaging the distribution of the .sup.19F-labeled targeting molecule in the subject by MRI or imaging the distribution of the .sup.18F-labeled targeting molecule in the subject by PET. 2. The method of claim 1, wherein the targeting molecule is selected from the group consisting of a protein, a peptide, an antibody, a monoclonal antibody, a bispecific antibody, a multispecific antibody, an antibody fusion protein, an antigen-binding antibody fragment, an affibody and a targetable construct. 3. The method of claim 2, wherein the antibody is selected from the group consisting of hR1 (anti-IGF-1R), hPAM4 (anti-pancreatic cancer 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) and hMN-3 (anti-CEACAM6). 4. The method of claim 2, wherein the antibody is selected from the group consisting of Ab124 (anti-CXCR4), Ab125 (anti-CXCR4), abciximab (anti-glycoprotein IIb/IIIa), alemtuzumab (anti-CD52), bevacizumab (anti-VEGF), cetuximab (anti-EGFR), gemtuzumab (anti-CD33), ibritumomab (anti-CD20), panitumumab (anti-EGFR), rituximab (anti-CD20), tositumomab (anti-CD20), trastuzumab (anti-ErbB2), abagovomab (anti-CA-125), adecatumumab (anti-EpCAM), atlizumab (anti-IL-6 receptor), benralizumab (anti-CD125), CC49 (anti-TAG-72), AB-PG1-XG1-026 (anti-PSMA), D2/B (anti-PSMA), tocilizumab (anti-IL-6 receptor), basiliximab (anti-CD25), daclizumab (anti-CD25), efalizumab (anti-CD11a), GA101 (anti-CD20), muromonab-CD3 (anti-CD3 receptor), natalizumab (anti-.alpha.4 integrin), omalizumab (anti-IgE), infliximab (anti-TNF-.alpha.), certolizumab pegol (anti-TNF-.alpha.), adalimumab (anti-TNF-.alpha.), and belimumab (anti-BLyS). 5. The method of claim 2, wherein the antibody fragment is selected from the group consisting of F(ab').sub.2, Fab', F(ab).sub.2, Fab, scFv and VHH (single domain antibody). 6. The method of claim 1, wherein the targeting molecule binds to a tumor-associated antigen (TAA). 7. The method of claim 5, 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-1-.alpha., AFP, PSMA, CEACAM5, CEACAM-6, c-met, B7, ED-B of fibronectin, Factor H, FHL-1, Flt-3, folate receptor, GROB, HMGB-1, hypoxia inducible factor (HIF), insulin-like growth factor-1 (ILGF-1), IFN-.gamma., IFN-.alpha., IFN-.beta., 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, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5, NCA-95, NCA-90, Ia, EGP-1, EGP-2, HLA-DR, tenascin, Le(y), RANTES, T101, TAC, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, TNF-.alpha., TRAIL receptor (R1 and R2), VEGFR, EGFR, P1GF, complement factors C3, C3a, C3b, C5a, and C5. 8. The method of claim 1, wherein the targeting molecule is somatostatin, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), bombesin, methotrexate, growth hormone, RGD (arginine-glycine-aspartic acid) or folic acid. 9. The method of claim 1, wherein the bifunctional chelating agent is selected from the group consisting of 1,4,7-triazacyclononane-1,4-diacetic acid-7-methyl phenyl-p-nitro; 1,4,7-triazacyclononane-1,4-diacetic acid-7-ethyl phenyl-p-nitro; 1,4,7-triazacyclononane-1,4-diacetic acid-7-methyl phenyl-p-amino; 1,4,7-triazacyclononane-1,4-diacetic acid-7-ethyl phenyl-p-amino; 1,4,7-triazacyclononane-1,4-diacetic acid-7-methyl phenyl-p-isothiocyanato; 1,4,7-triazacyclononane-1,4-diacetic acid-7-ethyl phenyl-p-isothiocyanato; 1,4,7-triazacyclononane-1,4-diacetic acid-7-butanoic acid; 1,4,7-triazacyclononane-1,4-diacetic acid-7-propanoic acid; 1,4,7-triazacyclononane-1,4-diacetic acid-7-hexanoic acid; 1,4,7-triazacyclononane-1-butylamine-4,7-diacetic acid; 1,4,7-triazacyclononane-1-propylamine-4,7-diacetic acid; 1,4,7-triazacyclononane-1-butyne-4,7-diacetic acid; 1,4,7-triazacyclononane-1-butylamido ethyl maleimide-4,7-diacetic acid; 1,4,7-triazacyclononane-1,4-diacetic acid-7-methyl phenyl acetamido ethyl maleimide; 1,4,7-triazacyclononane-1-butyl isothiocyanato-4,7-diacetic acid; 1,4,7-triazacyclononane-1-butyl azido-4,7-diacetic acid; 1,4,7-triazacyclononane-1-ethanol-4,7-diacetic acid; 1,4,7-triazacyclononane-1-propanol-4,7-diacetic acid; and 1,4,7-triazacyclononane-1-butanol-4,7-diacetic acid. 10. The method of claim 1, wherein M is aluminum. 11. The method of claim 1, wherein multiple copies of the bifunctional chelating agent are attached to the targeting molecule. 12. The method of claim 1, wherein the targeting molecule binds to cancer cells and the method is used to image tumors. 13. The method of claim 1, wherein the targeting molecule binds to a cell surface receptor and the method is used to image the distribution of the receptor.

Details for Patent 8,758,726

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Centocor Ortho Biotech Products, L.p.	ORTHOCLONE OKT3	muromanab-cd3	Injection	103463	09/14/1992		2027-01-11
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2027-01-11
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Novartis Pharmaceuticals Corporation	SIMULECT	basiliximab	For Injection	103764	01/02/2003		2027-01-11