Claims for Patent: 8,535,639

Summary for Patent: 8,535,639

Title:	Trifunctional imaging agent for monoclonal antibody tumor-targeted imaging
Abstract:	The present invention relates to trifunctional imaging agents that include an antibody for cell targeting, as well as a chelating moiety for sequestering radioisotopes and a fluorescing moiety for imaging. The invention also provides methods using the conjugates for medical diagnostic imaging.
Inventor(s):	Brechbiel; Martin W. (Annandale, VA), Xu; Heng (Rockville, MD), Baidoo; Kwamena (Reisterstown, MD)
Assignee:	The United States of America, as represented by the Secretary of the Department of Health and Human Services (Washington, DC) N/A (N/A)
Application Number:	12/667,790
Patent Claims:	1. A signaling agent of formula (I): ##STR00008## wherein Y' is a chelating moiety that is complexed with a radioisotope; Z' is a fluorescent dye covalently bonded to L; X is C.sub.1-C.sub.8 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; and L is an .alpha.-amino acid residue. 2. The signaling agent of claim 1, wherein X is selected from the group consisting of C.sub.2-C.sub.5 alkyl, cyclohexyl-C.sub.1-C.sub.4 alkyl, phenyl, and phenyl-C.sub.1-C.sub.4 alkyl. 3. The signaling agent of claim 1, wherein the .alpha.-amino acid residue is selected from the group consisting of glycine, alanine, valine, and lysine. 4. The signaling agent of claim 1, wherein Y' is selected from the group consisting of CHX-A'' (N-[(R)-2-amino-3-(p-aminophenyl)propyl ]-trans-(S,S) -cyclohexane-1,2-diamine-N,N,N',N, ''N''-pentaacetic acid), 1B4M (2-(4-aminobenzyl)-6-methyl-diethylenetriaminepentaacetic acid)), 1B4M-DTPA (2-(p-aminobenzyl)-6-methyl-1,4,7-triaminoheptane-N,N',N''-pent- aacetic acid), C-DOTA (2-(p-aminobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N,''N'''-tetraacet- ic acid), PA-DOTA (1,4,7,10-tetraaza-N-(1-carboxy-3-(4-nitrophenyl)propyl)-N',N'',N'''-tris- (acetic acid) cyclododecane), and TCMC (2-(p-aminobenzyl)-1,4,7,10-tetraazacyclododecane-N,N'N, ''N'''-tetracarboxamide). 5. The signaling agent of claim 1, wherein the radioisotope is selected from the group consisting of .sup.213Bi, .sup.212Bi, .sup.212pb, .sup.203Pb, .sup.225Ac, .sup.177Lu, .sup.99mTc, .sup.111In, .sup.124I, .sup.123I, .sup.186Re, .sup.201Tl, .sup.3He, .sup.166Ho, .sup.86Y, .sup.64Cu, .sup.89Zr, .sup.66Ga,.sup.68Ga, and .sup.67Ga. 6. The signaling agent of claim 5, wherein the radioisotope is selected from the group consisting of .sup.64Cu, .sup.86Y, .sup.89Zr, .sup.111In, and .sup.203Pb. 7. The signaling agent of claim 1, wherein the fluorescent dye is selected from the group consisting of an Alexa Fluor dye, a cyanine dye, rhodamine, coumarin, pyrene, dansyl, fluorescein, fluorescein isothiocyanate, carboxyfluorescein diacetate succinimidyl ester, an isomer of fluorescein, R-phycoerythrin, tris(2',2-bipyridyl)dichlororuthenium(II) hexahydrate, Fam, VIC.RTM., NED.TM., ROX.TM. (carboxy-X-rhodamine), calcein acetoxymethylester, DiIC.sub.12, and anthranoyl. 8. The signaling agent of claim 7, wherein the cyanine dye is Cy5.5, Cy5, or Cy7. 9. An imaging agent comprising (a) a signaling agent of formula (I): ##STR00009## wherein Y' is a chelating moiety that is complexed with a radioisotope; Z' is a fluorescent dye covalently bonded to L; X is C.sub.1-C.sub.8 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; and L is an .alpha.-amino acid residue; and (b) a targeting vector conjugated to the reactive maleimide group of the signaling agent. 10. The imaging agent of claim 9, wherein the targeting vector binds to a cell surface antigen associated with a disease. 11. The imaging agent of claim 9, wherein the targeting vector is a peptide, a monoclonal antibody, or a monoclonal antibody fragment. 12. The imaging agent of claim 9, wherein the targeting vector is trastuzumab. 13. A composition comprising (a) at least one signaling agent of claim 1; and (b) a carrier. 14. A composition comprising (a) at least one imaging agent of claim 9; and (b) a carrier. 15. A method of imaging a cancer cell in a mammal comprising (a) administering to the mammal intravenously the imaging agent of claim 9; (b) contacting a surface receptor of the cancer cell with the targeting vector of the imaging agent; and (c) observing a fluorescence emission from the fluorescent dye moiety or detecting an emission from the chelating moiety of the imaging agent by spectroscopy. 16. The method of claim 15, wherein the spectroscopy is single photon emission computed spectroscopy (SPECT) or positron emission tomography (PET). 17. The method of claim 15, wherein the cancer cell over-expresses HER 1 and/or HER2. 18. The method of claim 15, wherein the cancer cell is an epithelial cancer cell. 19. The method of claim 18, wherein the epithelial cancer cell is breast carcinoma, ovarian carcinoma, pancreatic carcinoma, or colorectal carcinoma. 20. A method for obtaining a diagnostic image of a mammal comprising (a) administering to the mammal the imaging agent of claim 9, in an amount effective to provide an image; and (b) exposing the mammal to an energy source, whereupon a diagnostic image of the mammal is obtained. 21. The method of claim 20, wherein the diagnostic image is a single photon emission computed spectroscopy (SPECT) image or a positron emission tomography (PET) image. 22. The imaging agent of claim 9, wherein the a-amino acid residue is selected from the group consisting of glycine, alanine, valine, and lysine.

Details for Patent 8,535,639

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2027-07-17
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2027-07-17
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2027-07-17