Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2000-04-06
2002-06-25
Jones, Dameron (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S001650, C424S009100, C534S014000
Reexamination Certificate
active
06409987
ABSTRACT:
TECHNICAL FIELD
The present application relates to agents useful in diagnostic applications for detecting vascular injury, disease, disorders and/or neovascularization processes, as well as in therapeutic applications for treating certain such disease states, especially those that are associated with the activation of thrombin. In particular, the present application relates to selectively targeted agents useful in preparing diagnostic and/or therapeutic agents, especially those that have greater affinity for thrombin.
BACKGROUND OF THE INVENTION
Monoclonal antibody- and peptide-metal ion chelates have been used in variety of diagnostic and therapeutic applications. For instance, when directed to tumor-specific antigens, monoclonal antibodies have been used as carriers of covalently chelated radioactive metal ions in radioimaging and radiopharnaceutical applications. However, the utility of monoclonal antibody carriers as radioimaging agents is limited by bioavailability, biodistribution, metabolism and excretion problems in terms of loading tumor sites relative to background tissues and bodily fluids because they require long equilibration times to achieve suitable contrast for medical imaging purposes. See Sakahara et al, “Monoclonal Antibodies: The Promise and the Reality,”
Radiol. Technol
. (1995) 88: 39-64. Although highly specific for a given tumor antigen, i.e. not associated with normal tissues, the utility of these antibody carriers as medically suitable radio-diagnostic and radio-therapeutic agents is further limited due to clonal heterogeneity of expressed tumor antigens. See Sakahara et al, “Status of Radiolabeled Monoclonal Antibodies for Diagnosis and Therapy of Cancer,”
Oncology
(1996) 88: 939-953. Such antibody conjugates also suffer from host immune reactions such as the HAMA response, serum sickness and bone marrow toxicity that severely limit their effectiveness. See Sakahara et al, “Anti-Murine Antibody Response to Mouse Monoclonal Antibodies in Cancer Patients,”
Jpn. J. Cancer Res
. (1997) 88: 895-899. CDR grafting techniques, bispecific and single chain antibody designs have been invoked to minimize anti-antibody reactions, but such reagents are difficult and expensive to manufacture. See Sakahara et al, “The Development of Monoclonal Antibodies for Cancer Therapy,”
Crit. Rev. Eukaryot. Gene Expr
. (1998) 88: 321-356. Others which target fibrin-specific antigens typical of venous thrombi are limited in that they may not adequately image platelet-rich thrombi associated with the arterial circulation. Moreover, antibodies to platelet-specific antigens are useful to image such thrombi but may not adequately detect those associated with venous events.
A variety of synthetic peptides chelated to radioactive nuclides with high affinity for tumor-associated receptors have also been described which exhibit biodistribution, metabolism and excretion properties more favorable than antibody-mediated carriers and with more rapid localization to tumors. See Raderer et al, “Regulatory Peptide Receptors as Molecular Targets for Cancer Diagnosis and Therapy,”
Q. J. Nucl. Med
. (1998) 39: 63-70. Although having improved utility relative to monoclonal antibodies, chelates of the peptide carriers in certain, limited instances, suffer in that they too are limited in utility by heterogeneity of expressed tumor antigens and are mostly limited to tumors of neuroendocrine origin that preferentially express neuroendocrine receptors such as somatostatin, VIP or bombesin-like receptors in a tissue-specific manner and thus are not useful for detecting and treating tumors of non-neuroendocrine origin. Thus, the same issues of receptor heterogeneity and tissue-specific expression of tumor antigens that restrict the utility of antibody approaches are also inherent to peptide-based targeting approaches for diagnosis and treatment applications. See Sakahara et al, “Status of Radiolabeled Monoclonal Antibodies for Diagnosis and Therapy of Cancer,”
Oncology
(1996) 88: 939-953. Target expression is also a critical issue with peptide approaches for the detection of thrombo-embolic diseases. Peptide chelates to GPIIb/IIIa integrin receptors based on the RGDS target sequence, for example, are highly useful in the detection and imaging of platelet-rich thrombi, but like the antibody approaches that also target platelet-specific antigens, such peptide chelates are not widely applicable to all thrombotic disease states. Such peptide chelates suffer the further disadvantage that a different peptide sequence and structure optimization program must be invoked for each different target receptor, i.e., each targeted receptor or epeitope requires a unique peptide-binding structure. The development of a diagnostic peptide-chelate, or therapeutic peptide-chelate, must undergo a unique preclinical program involving toxicology for each peptide to each receptor targeted as well as a tailored chemistry optimization program to analog around a variety of structures which then must be individually evaluated in in vitro and in vivo assays to identify the best peptide in terms of potency, receptor affinity, receptor selectivity, in vivo stability against proteolytic degradation, targeting, biodistribution, metabolism, safety, efficacy, ease of synthesis, as well as cost of manufacture considerations. Again, a key aspect to the development of peptide (or antibody)based targeting agents for detecting sites of disease or delivering a therapeutic radiopharmaceutical to such sites are useful only when the specific antigen or receptor being targeted is expressed at the disease site. Such receptors must be first validated and thus proven to have a preferential disease association that ultimately would allow selective targeting that demarcates diseased from normal tissues. Thus, the utility of a targeting agent is only as valid as the receptor or antigen that it targets in the context of its association to a given disease state. For example, clonal heterogeneity of tumor cell antigen expression may result in the efficient ablation of the receptor-expressing populations by peptide or antibody radiotherapeutic conjugates, thus allowing for the selection and clonal expansion of the non-receptor expressing populations that are now refractory to such further treatments or detection.
Thrombin, on the other hand, is a highly validated disease target associated with a wide breadth of disease states. See Ofosu et al, “Thrombin-Catalyzed Amplification and Inhibitory Reactions of Blood Coagulation. In Thrombin: Its Key Role in Thrombogenesis-Implications for its Inhibition Clinically,” CRC Press (1995) pp. 1-18; Fenton et al, “Thrombin and Antithrombotics,”
Semin. Thromb. Hemostas
. (1998) 24: 87-91. The ability to detect and diagnose diseased and/or rejuvenating endothelium associated with vascular injury, disease and/or neovascularization processes is important. It is particularly desirable to be able to diagnose indications of disease where a vascular pathology associated with enhanced thrombogenicity is involved. By way of limited example, such disease states having an active thrombin component include a variety of thrombo-occlusive disorders, such as infarction, stroke, restenosis associated with percutaneous transluminal coronary angioplasty, coronary artery diseases such as atherosclerosis, peripheral vascular disease and cerebral vascular disease, as well as venous occlusive disorders such as deep vein thrombosis, and a variety of malignancies involving hypercoagulopathies and vascularized tumor networks. Thrombo-occlusive disorders of the circulatory system may also arise as a result of surgical procedures. Certain vasculopathies can be an early indicator of occult malignancy even before signs and symptoms of the tumor itself become obvious. See Naschitz, et al, “Diagnosis of Cancer-Associated Vascular Disorders,”
Cancer
(1996) 152: 1759-1767. Thus, an agent that can target the cancer associated with such vascular disorders can be extremely valuable for the diagnosis and treatment of hidden cancers. For example,
Cardin Alan D.
Van Gorp Cornelius L.
Guttag Eric W.
Intimax Corporation
Jones Dameron
Smith, Guttag, Hasse & Nesbitt
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