| Monoclonal antibody hpam4 -> Monitor Keywords |
|
|
 
Monoclonal antibody hpam4Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory Compositions, Attached To Antibody Or Antibody Fragment Or Immunoglobulin; DerivativeMonoclonal antibody hpam4 description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080050311, Monoclonal antibody hpam4. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 60/388,314, filed Jun. 14, 2002, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0002] This invention relates to monovalent and multivalent, monospecific antibodies and to multivalent, multispecific antibodies. Specifically, the present invention relates to a MUC1 antigen specific antibody designated PAM4. The invention further relates to humanized and human PAM4 antibodies and fragments thereof, and the use of such antibodies and fragments thereof in diagnosis and therapy. [0003] In one embodiment, the antibodies of the present invention have one or more identical binding sites, wherein each binding site has an affinity toward a target antigen or an epitope on a target antigen. In another embodiment, the antibodies of the present invention have two or more binding sites which have an affinity toward the same or different epitopes on a target antigen or the same or different target antigens, or at least one binding site has an affinity toward a target antigen and at least one binding site has an affinity toward a hapten. The present invention also describes recombinant vectors useful for expressing the antibodies described herein in a host. BACKGROUND OF THE INVENTION [0004] The pancreas produces insulin to assist the body in converting glucose to energy and enzymes to assist the body in digesting food. Pancreatic cancer is a malignant growth of the pancreas that mainly occurs in the cells of the pancreatic ducts. This disease is the ninth most common form of cancer, yet it is the fourth and fifth leading cause of cancer deaths in men and women, respectively. Cancer of the pancreas is almost always fatal, with a five-year survival rate that is less than 3%. [0005] The most common symptoms of pancreatic cancer include jaundice, abdominal pain, and weight loss, which, together with other presenting factors, are nonspecific in nature. Thus, diagnosing pancreatic cancer at an early stage of tumor growth is often difficult and requires considerable suspicion and extensive diagnostic work-up, often times including exploratory surgery. Endoscopic ultrasonography and computed tomography are the best noninvasive means available today for diagnosis of pancreatic cancer. However, reliable detection of small tumors, as well as differentiation of pancreatic cancer from focal pancreatitis, is troublesome. Unfortunately, the vast majority of patients are presently diagnosed at a late stage when the tumor has already extended outside of the capsule to invade surrounding organs and/or has metastasized extensively. Gold et al., Crit. Rev. Oncology/Hematology, 39:147-54 (2001). Late detection of the disease is common, and "early" pancreatic cancer diagnosis is rare in the clinical setting. [0006] Current treatment procedures available for pancreatic cancer have not led to a cure, nor to a substantially improved survival time. Surgical resection has been the only modality that offers a chance at survival. However, due to a large tumor burden, only 10% to 25% of patients are candidates for "curative resection." For those patients undergoing a surgical treatment, the five-year survival rate is still poor, averaging only about 10%. [0007] Early detection and diagnosis of pancreatic cancer, as well as appropriate staging of the disease, would provide an increased survival advantage. A number of laboratories are proceeding on the development of a diagnostic procedure based upon the release of a tumor-associated marker into the bloodstream as well as detection of the marker substance within biopsy specimens. The best tumor associated marker for pancreatic cancer has been the immunoassay for CA19.9. Elevated levels of this sialylated Lea epitope structure were found in 70% of pancreatic cancer patients but were not found in any of the focal pancreatitis specimens examined. However, CA19.9 levels were found to be elevated in a number of other malignant and benign conditions, so that currently the assay cannot be used for diagnosis. However, the assay is useful for monitoring, the continued increase in CA19.9 serum levels after surgery being indicative of a poor prognosis. Many other monoclonal antibodies (MAbs) have been reported with immunoassays for diagnosis in varying, stages of development. These include but are not limited to DUPAN2, SPAN1, B72.3, Ia3, and various anti-CEA antibodies. [0008] Man-made antibodies, in particular MAbs and engineered antibodies or antibody fragments, have been tested widely and shown to be of value in detection and treatment of pancreatic cancer, as well as other various human disorders, including cancers, autoimmune diseases, infectious diseases, inflammatory diseases, and cardiovascular diseases [Filpula and McGuire, Exp. Opin. Ther. Patents (1999) 9: 231-245]. The clinical utility of an antibody or an antibody-derived agent is primarily dependent on its ability to bind to a specific targeted antigen associated with a specific disorder. Selectivity is valuable for delivering a diagnostic or therapeutic agent, such as isotopes, drugs, toxins, cytokines, hormones, hormone antagonists, enzymes, enzyme inhibitors, oligonucleotides, growth factors, oligonucleotides, radionuclides, an angiogenesis inhibitor, or metals, to a target location during the detection and treatment phases of a human disorder, particularly if the diagnostic or therapeutic agent is toxic to normal tissue in the body. Radiolabeled antibodies have been used with some success in numerous malignancies, including ovarian cancer, colon cancer and lymphoma. This technology may also prove useful for pancreatic cancer. However, other than the application of anti-CEA antibodies and B72.3, little clinical information exists. [0009] The potential limitations of such antibody systems are discussed in Goldenberg, The American Journal of Medicine, 94: 298-299 (1993). The important parameters in the detection and treatment techniques are the amount of the injected dose specifically localized at the site(s) where target cells are present and the uptake ratio, i.e. the ratio of the concentration of specifically bound antibody to that of the radioactivity present in surrounding normal tissues. When an antibody is injected into the blood stream, it passes through a number of compartments as it is metabolized and excreted. The antibody must be able to locate and bind to the target cell antigen while passing through the rest of the body. Factors that control antigen targeting include location, size, antigen density, antigen accessibility, cellular composition of pathologic tissue, and the pharmacokinetics of the targeting antibodies. Other factors that specifically affect tumor targeting by antibodies include expression of the target antigens, both in tumor and other tissues, and bone marrow toxicity resulting from the slow blood-clearance of the radiolabeled antibodies. The amount of targeting antibodies accreted by the targeted tumor cells is influenced by the vascularization and barriers to antibody penetration of tumors, as well as intratumoral pressure. Non-specific uptake by non-target organs such as the liver, kidneys or bone-marrow is another potential limitation of the technique, especially for radioimmunotherapy, where irradiation of the bone marrow often causes the dose-limiting toxicity. [0010] One suggested approach for delivering agents to a target site, referred to as direct targeting, is a technique designed to target specific antigens with antibodies carrying diagnostic or therapeutic radioisotopes. In the context of tumors, the direct targeting approach utilizes a radiolabeled anti-tumor monospecific antibody that recognizes the target tumor through its antigens. The technique involves injecting the labeled monospecific antibody into the patient and allowing the antibody to localize at the target tumor to obtain diagnostic or therapeutic benefits. The unbound antibody clears the body. This approach can be used to diagnose or treat additional mammalian disorders. [0011] Another suggested solution, referred to as the "Affinity Enhancement System" (AES), is a technique especially designed to overcome deficiencies of tumor targeting by antibodies carrying diagnostic or therapeutic radioisotopes [U.S. Pat. No. 5,256,395 (1993), Barbet et al., Cancer Biotherapy & Radiopharmaceuticals 14: 153-166 (1999)]. The AES utilizes a radiolabeled divalent hapten and an anti-tumor/anti-hapten bispecific antibody that recognizes both the target tumor and the radioactive hapten. Haptens with higher valency and antibodies with higher specificity may also be utilized for this procedure. The technique involves injecting the antibody into the patient and allowing it to localize at the target tumor. After a sufficient amount of time for the unbound antibody to clear from the blood stream, the radiolabeled hapten is administered. The hapten binds to the antibody-antigen complex located at the site of the target cell to obtain diagnostic or therapeutic benefits, while the unbound hapten rapidly clears from the body. Barbet mentions the possibility that a bivalent hapten may crosslink with a bispecific antibody, when the latter is bound to the tumor surface. As a result, the radiolabeled complex is more stable and stays at the tumor for a longer period of time. This system can be used to diagnose or treat mammalian disorders. [0012] There remains a need in the art for production of multivalent, monospecific antibodies that are useful in a direct targeting system and for production of multivalent, multispecific antibodies that are useful in an affinity enhancement system. Specifically, there remains a need for a antibody that performs as a useful diagnostic tool for pancreatic cancer and that exhibits enhanced uptake at targeted antigens, decreased concentration in the blood, and optimal protection of normal tissues and cells from toxic pharmaceuticals. SUMMARY OF THE INVENTION [0013] Contemplated in the present invention is an antibody, fusion protein, and fragments thereof that bind a domain located between the amino terminus and start of the repeat domain of MUC1. In a preferred embodiment the antibody, fusion protein, or fragment thereof is a PAM4 antibody. The PAM4 antibody, fusion protein, or fragment thereof of the present invention is derived by immunization and/or selection with mucin, and is preferably reactive against mucin of pancreatic cancer. Accordingly, the PAM4 antibody, fusion protein, and fragments thereof of the present invention preferably bind an antigen associated with pancreatic cancer cells. [0014] In a preferred embodiment, the PAM4 antibody or fragment thereof is humanized or fully human, or the PAM4 fusion protein comprises a humanized or fully human PAM4 antibody or fragment thereof. Also preferred, the PAM4 antibody, fusion protein, and fragments thereof can be conjugated to at least one therapeutic and/or diagnostic agent. [0015] Contemplated herein is a humanized PAM4 antibody or fragment thereof comprising the complementarity-determining regions (CDRs) of a murine PAM4 MAb and the framework (FR) regions of the light and heavy chain variable regions of a human antibody and the light and heavy chain constant regions of a human antibody, wherein the CDRs of the light chain variable region of the humanized PAM4 MAb comprise CDR1 comprising an amino acid sequence of SASSSVSSSYLY; CDR2 comprising an amino acid sequence of STSNLAS; and CDR3 comprising an amino acid sequence of HQWNRYPYT; and the CDRs of the heavy chain variable region of the humanized PAM4 MAb comprise CDR1 comprising an amino acid sequence of SYVLH; CDR2 comprising an amino acid sequence of YINPYNDGTQYNEKFKG and CDR3 comprising an amino acid sequence of GFGGSYGFAY. In a preferred embodiment, the FRs of the light and heavy chain variable regions of the humanized PAM4 antibody or fragment thereof comprise at least one amino acid substituted from the corresponding FRs of a murine PAM4 MAb. Still preferred, the humanized PAM4 antibody or fragment thereof of comprises at least one amino acid selected from the group consisting of amino acid residues 5, 27, 30, 38, 48, 66, 67, and 69 of the murine heavy chain variable region of FIG. 1B, PAM4 VH amino acid sequence. Also preferred, the humanized PAM4 antibody or fragment thereof wherein said amino acid from said murine MAb is at least one amino acid selected from the group consisting of amino acid residues 21, 47, 59, 60, 85, 87, and 100 of the murine light chain variable region FIG. 1A, PAM4V.kappa. sequence. Most preferably, the humanized PAM4 antibody or fragment thereof comprises the PAM4 V.kappa. nucleotide sequence of FIG. 1A and the PAM4 VH nucleotide sequence of FIG. 1B and/or comprises a hPAM4 V.sub.H amino acid sequence of FIG. 4A and a hPAM4 V.kappa. amino acid sequence of FIG. 4B. [0016] Another embodiment of the present invention is a cancer cell targeting diagnostic immunoconjugate comprising an antibody component that comprises an antibody or fragment thereof of any one of the antibodies, fusion proteins, or fragments thereof of the present invention, wherein the antibody, fusion protein, or fragment thereof is bound to at least one diagnostic/detection agent. [0017] Preferably, the diagnostic/detection agent is selected from the group comprising a radionuclide, a contrast agent, and a photoactive diagnostic/detection agent. Still preferred, the diagnostic/detection agent is a radionuclide with an energy between 20 and 4,000 keV or is a radionuclide selected from the group consisting of .sup.110In, .sup.111In, .sup.177Lu, .sup.118F, .sup.52Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.86Y, .sup.90Y, .sup.89Zr, .sup.94mTc, .sup.94Tc, .sup.99mTc, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.154-158Gd, .sup.32P, .sup.11C, .sup.13N, .sup.15O, .sup.186Re, .sup.188Re, .sup.51Mn, .sup.52mMn, .sup.55Co, .sup.72As, .sup.75Br, .sup.76Br, .sup.82mRb, .sup.83Sr, or other gamma-, beta-, or positron-emitters. Also preferred, the diagnostic/detection agent is a paramagnetic ion, such as the a metal comprising chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) and erbium (III), or a radioopaque material, such as barium, diatrizoate, ethiodized oil, gallium citrate, iocarmic acid, iocetamic acid, iodamide, iodipamide, iodoxamic acid, iogulamide, iohexyl, iopamidol, iopanoic acid, ioprocemic acid, iosefamic acid, ioseric acid, iosulamide meglumine, iosemetic acid, iotasul, iotetric acid, iothalamic acid, iotroxic acid, ioxaglic acid, ioxotrizoic acid, ipodate, meglumine, metrizamide, metrizoate, propyliodone, and thallous chloride. [0018] Also preferred, the diagnostic/detection agent is a fluorescent labeling compound selected from the group comprising fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine, a chemiluminescent labeling compound selected from the group comprising luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt and an oxalate ester, or a bioluminescent compound selected from the group comprising luciferin, luciferase and aequorin. In another embodiment, the diagnostic immunoconjugates of the present invention are used in intraoperative, endoscopic, or intravascular tumor diagnosis. [0019] Another embodiment of the present invention is a cancer cell targeting therapeutic immunoconjugate comprising an antibody component that comprises an antibody or fragment thereof of any one of the antibodies, fusion proteins, or fragments thereof of the present invention, wherein the antibody, fusion protein, or fragment thereof is bound to at least one therapeutic agent. [0020] Preferably, the therapeutic agent is selected from the group consisting of a radionuclide, an immunomodulator, a hormone, a hormone antagonist, an enzyme, oligonucleotide, an enzyme inhibitor, a photoactive therapeutic agent, a cytotoxic agent, an angiogenesis inhibitor, and a combination thereof. Continue reading about Monoclonal antibody hpam4... Full patent description for Monoclonal antibody hpam4 Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Monoclonal antibody hpam4 patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Monoclonal antibody hpam4 or other areas of interest. ### Previous Patent Application: Antibodies and immunoconjugates and uses therefor Next Patent Application: Radiolabeled dihydrotetrabenazine derivatives and their use as imaging agents Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Monoclonal antibody hpam4 patent info. IP-related news and info Results in 0.30829 seconds Other interesting Feshpatents.com categories: Accenture , Agouron Pharmaceuticals , Amgen , AT&T , Bausch & Lomb , Callaway Golf 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
