US00606883OA United States Patent (19) 11 Patent Number: 6,068,830 Diamandis et al. (45) Date of Patent: May 30, 2000 54) LOCALIZATION AND THERAPY OF FOREIGN PATENT DOCUMENTS NON-PROSTATIC ENDOCRINE CANCER 0217577 4/1987 European Pat. Off.. WITH AGENTS DIRECTED AGAINST 0453082 10/1991 European Pat. Off.. PROSTATE SPECIFIC ANTIGEN WO 92/O1936 2/1992 European Pat. Off.. WO 93/O1831 2/1993 European Pat. Off.. 75 Inventors: Eleftherios P. Diamandis, Toronto; Russell Redshaw, Nepean, both of OTHER PUBLICATIONS Canada Clinical BioChemistry vol. 27, No. 2, (Yu, He et al), pp. 73 Assignee: Nordion International Inc., Canada 75-79, dated Apr. 27, 1994. Database Biosis BioSciences Information Service, AN 21 Appl. No.: 08/569,206 94:393008 & Journal of Clinical Laboratory Analysis, vol. 8, No. 4, (Yu, He et al), pp. 251-253, dated 1994. 22 PCT Filed: Jul. 14, 1994 Bas. Appl. Histochem, Vol. 33, No. 1, (Papotti, M. et al), 86 PCT No.: PCT/CA94/00392 Pavia pp. 25–29 dated 1989. S371 Date: Apr. 11, 1996 Primary Examiner Yvonne Eyler S 102(e) Date: Apr. 11, 1996 Attorney, Agent, or Firm-Banner & Witcoff, Ltd. 87 PCT Pub. No.: WO95/02424 57 ABSTRACT It was discovered that prostate-specific antigen is produced PCT Pub. Date:Jan. 26, 1995 by non-proStatic endocrine cancers. It was further discov 30 Foreign Application Priority Data ered that non-prostatic endocrine cancers with Steroid recep tors can be stimulated with Steroids to cause them to produce Jul. 14, 1993 GB United Kingdom ................... 93.14623 PSA either initially or at increased levels. This invention 51) Int. Cl." .......................... A61K 51/00; A61K 49/00; relates to the imaging of non-prostatic endocrine cancers by G01N 31/00; G01N 33/48 labelled biological binding units which bind to prostate 52 U.S. Cl. .................... 424/9.34; 424/1.49; 424/9.323; Specific antigen in an imaging procedure, Such as, radioim 435/723; 436/64 aging or magnetic resonance imaging. Further, the PSA 58 Field of Search .......................... 435/7.23; 424/1.49, binding units may be constructed to deliver a toxic agent, 424/9.34, 9.323; 436/64 Such as a radioisotope, toxin or a drug to provide endocrine cancer therapy. Another aspect of the invention is passive 56) References Cited immunotherapy against endocrine cancers by treatment with PSA-binding units. U.S. PATENT DOCUMENTS 5,162,504 11/1992 Horoszewicz ........................ 530/388.2 7 Claims, 4 Drawing Sheets U.S. Patent May 30, 2000 Sheet 1 of 4 6,068,830 6 A Free PSA 2 45000 E 5 CS d S 4 35000 g 35 25000 1 15000 SD O o O 1 O 20 30 40 50 60 5000 Fraction Number F. G. A. B Free PSA 45OOO ACT-PSA t 35OOO 25000 l i 15000 adtw. 5OOO 1O 20 30 40 50 60 Fraction Number F. G. B. U.S. Patent May 30, 2000 Sheet 2 of 4 6,068,830 PSA 4.4 U.S. Patent May 30, 2000 Sheet 3 of 4 6,068,830 1O 1. S 1 O) 2 P CC { ... 1 O1 -11 -10 -9 -8 -7 -6 Log(Steroid Concentration,mol/L) F. G. 3. U.S. Patent May 30, 2000 Sheet 4 of 4 6,068,830 & - - - - - - - - - - - - - - - - & & S.& 6,068,830 1 2 LOCALIZATION AND THERAPY OF NON Direct approaches to radionuclide imaging include radio PROSTATIC ENDOCRINE CANCER WITH labelled chemotherapeutic agents, simple ionic Substances, AGENTS DIRECTED AGAINST PROSTATE metabolite imaging, immunologic and receptor imaging. SPECIFIC ANTIGEN The use of radiolabelled chemotherapeutic agents, Such as bleomycin, have not demonstrated clinical value (14). ''Ga FIELD OF THE INVENTION citrate is the most commonly used simple ionic tracer for This invention relates to the localization and therapy of tumor imaging, however it localizes in other pathologies and non-prostatic endocrine cancers by agents that have been is non specific (15, 16, 17, 18). Metabolite imaging carried constructed to target prostate specific antigen (PSA). out with positron emitting radionuclides such as F fluorodeoxyglucose, 'C-methionine and 'C-thymidine BACKGROUND OF THE INVENTION provides tumor metabolism information that has been shown Cancer of the breast is the most common cause of cancer to be clinically valuable for disease staging (19, 20, 21). death in middle aged women in Europe and North America The receptor imaging of breast cancer has been attempted and both its incidence and mortality are on the increase by Several approaches. Spicer et al. (22) and Hochberg (23) (1-5). The predominant indications for breast tumor imag 15 and others (24-29) have developed radiolabelled estradiols ing are: detecting the presence of tumor, localizing Sites of and have been able to demonstrate imaging in estrogen disease, and following the effects of therapy (6). Trends in receptor positive breast cancers. It has been postulated that Scintigraphic imaging have been towards developing imag a therapeutic response could result with Auger electrons ing pharmaceuticals to provide quantitative information on from 'I or 'I radiolabelled estradiols (30,31), or from B the pathophysiological characteristics of a tumor, Such as its emitting radioisotopes such as Re conjugated to proges anaplasticity, or likely response to a given therapy (7). For terone (32). A problem with receptor based imaging is the example, to determine Via Scintigraphic imaging how a interference that estrogen receptor antagonists, Such as patients breast cancer will respond to the administration of a growth Suppressor, Such as Somatostatin, or the estrogen tamoxifen, may have in the clinical environment. receptor antagonist tamoxifen (8). Diamandis in PCT Appli 25 It is known that proteins, Such as antibodies, can be cation CA 94/00267 has shown that the presence of PSA in developed against Specific antigens that are either produced breast tumors, as measured by in vitro methods, has prog or associated with tumors, can be used to localize tumors. nostic value. Thus, imaging of these tumors may not only U.S. Pat. No. 3,927,193 to Hansen et al. (33) discloses a reveal occult disease, but may also provide clinically valu process whereby antibodies to carcinoembryonic antigen able pathophysiological information. (CEA) and labelled with 'I and "I were used to image the location of tumors present in hamsters. From this work it Tumor imaging is commonly carried out using a gamma was proposed that the location of a tumor in a human could emitting radionuclide conjugate and a Scintillation gamma be determined by in Vivo administration of a parenteral camera, or with a positron emitting radiopharmaceutical and Solution containing an antibody-radioisotope conjugate fol a positron or PET camera, or with a magnetopharmaceutical lowed by imaging by a gamma camera. Goldenberg et al. and a magnetic resonance imaging device. The Scintillation 35 camera, also known as an Anger camera, consists of a reported Success in clinical trials of tumor detection and detector head, and a display console. The Anger camera head localization by Scintillation Scanning of patients that is composed of Sodium iodide crystals that absorb gamma received radiolabelled antibodies to CEA (34). rays and emits the absorbed energy as flashes of light Based on the original work of Milstein and Kohler (35), Scintillations that are proportional in brightness to the energy 40 monoclonal antibodies have been developed against a vari absorbed. In a gamma camera the Sodium iodide crystals are ety of tumour antigens such as CA 19.9, CA 125, melanoma coupled to photomultiplier tubes that convert light pulses asSociated antigens, TAG 72, C. fetal protein, ferritin, into electronic pulses. These voltages are translated via a choriogonadotropin, prostatic acid phosphatase, and PSA for computing circuit to a cathode ray tube. The data from the radioimmunoimaging and therapy. camera head may be in either analog or digital form that can 45 Several investigators have reported on the development of be stored in a computer and can reconstruct the data to monoclonal antibodies against epitopes of various malignant provide an image. Single-photon emission computed tomog prostate cell components (36, 37, 38, 39, 40). Moveover, raphy (SPECT) imaging involves the use of a gamma PSA was purified and well characterized and found to have Scintillation camera where multiple images, typically a molecular weight in the range of 34,000 (41). PSA is used encompassing 180 or 360, around the body are taken and 50 widely as a tumor marker for in vitro based analyses for the computer issued to reconstruct multiple tomograms in diagnostic and monitoring purposes of prostatic carcinoma. coronal, Sagittal, and transverse projections. In PET imaging U.S. Pat. No. 5,162,504 describes monoclonal antibodies the positron radionuclide collides with an electron causing that have been developed to recognize malignant prostate annihilation of the particles and creating two photons that epithelium. These antibodies were developed as diagnostic travel in 180 opposite directions. The PET system is 55 and prognostic tools for the detection of cancer of the designed to capture opposite sides and register the count at prostate, not as embodies in this invention, for the detection precisely the same time. A computer is used to manipulate of cancers not associated with the prostate. Until the dis the data and then reconstruct a croSS Sectional image from covery reported by Diamandis in International Application this information. PCT CA94/00267, it was thought that PSA only occurred in There are a number of approaches to breast tumor imag 60 men and was only produced by prostate tissue. ing that may be divided into two groups: indirect and direct. To image breast tumors researchers have developed anti Indirect techniques, are generally utilized to locate meta bodies directed against TAG 72, CA-3, CEA, EGF-R, Static disease by recognizing the Secondary effects of tumor LASA-P, and other glycoproteins associated with breast within an organ System.