Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• This disclosure relates to methods of determining the effectiveness of anti- inflammatory compounds in reducing incidence of myocardial infarction. Methods of prophylaxis against myocardial infarctions which exhibit CK-MB levels greater than about 50 nano-grams/ml in a subject are also described.
• Coronary artery disease is often characterized by lesions or occlusions in the coronary arteries which may result in inadequate blood flow to the myocardium, or myocardial ischemia, which is typically responsible for such complications as angina pectoris, necrosis of cardiac tissue (myocardial infarction), and sudden death.
• coronary artery disease may be treated by the use of drugs and by modifications in behavior and diet.
• dilatation of coronary arteries may be achieved by such procedures as angioplasty, laser ablation, atherectomy, catheterization, and intravascular stents.
• CABG coronary artery bypass grafting
• a vessel segment to one or more of the coronary arteries.
• a reversed segment of the saphenous vein may be grafted at one end of the ascending aorta as an arterial blood source and at the other end to a coronary artery at a point beyond the arterial occlusion.
• the internal mammary artery is located in the thoracic cavity adjacent the sternum and is likewise suitable for grafting to a coronary artery, such as the left anterior descending artery.
• a cardiopulmonary bypass (CPB) machine receives deoxygenated blood from the patient's body, adds oxygen and various nutrients to the blood, and pumps the oxygenated blood back into the patient's body.
• CPB cardiopulmonary bypass
• CPB a systemic inflammatory response that causes tissue injury and contributes to significant perioperative and long-term clinical morbidity.
• CPB exposure of blood to bioincompatible surfaces of the extracorporeal circuit, as well as tissue ischemia and reperfusion associated with the procedure, induces the activation of several major humoral pathways of inflammation.
• Clinical manifestations attributed to this systemic inflammatory response may include myocardial injury which may manifest as myocardial infarction (heart cell death) or as severe ventricular dysfunction requiring circulatory assist.
• CK creatine kinase
• M-subunit subunits commonly identified as the M-subunit and the B-subunit.
• CK-MB is associated with myocardial infarction, and is present in serum in only trace concentrations in the absence of such an episode (other isoenzymes CK- MM and CK-BB are found in skeletal muscle and brain cells). Appearance of CK-MB isoenzyme in serum is, therefore, indicative of myocardial infarction.
• h5G1.1-scFv potent complement inhibitory and anti-inflammatory activities were associated with significant reductions in postoperative CK-MB release, new cognitive deficits, and blood loss.
• a method of determining effectiveness of an anti-inflammatory compound in reducing incidence of post-CABG myocardial infarction includes administering an anti-inflammatory compound to a subject group including at least one patient undergoing a procedure involving cardiopulmonary bypass; comparing incidence of infarctions in the subject group to incidence of infarctions in a control sample of patients for a given peak CK-MB level in the blood (such as, for example, greater than 50 nano-grams/ml) in both groups; wherein a decrease in the incidence of infarctions in the subject group indicates effectiveness of the compound.
• a method of prophylaxis against myocardial infarctions which exhibit peak CK-MB levels greater than about 50 nano-grams/ml in a subject is provided.
• This method includes administering to the subject undergoing a procedure involving cardiopulmonary bypass an effective myocardial infarction reducing amount of an anti-inflammatory compound.
• Figure 1 is a graph summarizing the reduction of incidence of myocardial infarction which exhibit various CK-MB levels that was provided by an anti-C5 antibody, namely h5G1.1-scFv in a controlled, randomized clinical test of patients undergoing CABG with CPB.
• Figure 2 is a graphical presentation of the data of Table One showing the reduction in peak CK-MB values resulting from the use of h5G1.1-scFv. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
• the methods of determining effectiveness of an anti-inflammatory compound in reducing incidence of myocardial infarction in accordance with this disclosure includes the step of administering an anti-inflammatory compound to a subject group including at least one patient undergoing a procedure which involves cardiopulmonary bypass. Such procedures include, but are not limited to CABG and heart transplant.
• the level of CK-MB in the patients' blood is measured and the incidence of myocardial infarctions which exhibit peak CK-MB levels greater than about 50 nano-grams/ml is determined.
• the incidence of such infarctions in the subject group is then compared to the incidence of infarctions exhibiting a comparable level of CK-MB in a control sample of patients. A decrease in the incidence of infarctions in the subject group indicates effectiveness of the compound.
• Anti-inflammatory compounds which can be evaluated by the methods described herein include non-steroidal anti-inflammatory actives or drugs (NSAIDS).
• NSAIDS non-steroidal anti-inflammatory actives or drugs
• the NSAIDS can be selected from the following categories: propionic acid derivatives; acetic acid derivatives; fenamic acid derivatives; biphenylcarboxylic acid derivatives; and oxicams. All of these NSAIDS are fully described in the U.S. Pat. No. 4,985,459 to Sunshine et al., issued Jan. 15, 1991, incorporated by reference herein.
• propionic NSAIDS including, but not limited to aspirin, acetaminophen, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid.
• Another useful class of anti- inflammatory compounds include inhibitors of cyclooxygenase-1 (COX-1) and inhibitors of cyclooxygenase-2 (COX-2). Also useful are the steroidal anti-inflammatory drugs including hydrocortisone and the like. Particularly useful are anti-inflammatory compounds which reduce neutrophil activation or monocyte activation by greater than about 30%.
• Preferred anti-inflammatory compounds are compounds which bind to or otherwise block the generation and/or activity of complement components.
• a specific class of such compounds which are particularly useful are antibodies specific to a human complement component.
• the complement system acts in conjunction with other immunological systems of the body to defend against intrusion of cellular and viral pathogens.
• complement proteins There are at least 25 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors.
• the plasma proteins make up about 10% of the globulins in vertebrate serum.
• Complement components achieve their immune defensive functions by interacting in a series of intricate but precise enzymatic cleavage and membrane binding events.
• the resulting complement cascade leads to the production of products with opsonic, immunoregulat ⁇ ry, and lytic functions.
• a concise summary of the biologic activities associated with complement activation is provided, for example, In The Merck Manual, 16 th Edition.
• the complement cascade progresses via the classical pathway or the alternative pathway. These pathways share many components, and while they differ in their initial steps, they converge and share the same "terminal complement” components (C5 through C9) responsible for the activation and destruction of target cells.
• the classical complement pathway is typically initiated by antibody recognition of and binding to an antigenic site on a target cell.
• the alternative pathway is usually antibody independent, and can be initiated by certain molecules on pathogen surfaces.
• the lectin pathway is typically initiated with binding of mannose-binding lectin (MBL) to high mannose substrates. These pathways converge at the point where complement component C3 is cleaved by an active protease (which is different in each pathway) to yield C3a and C3b.
• Other pathways activating complement attack can act later in the sequence of events leading to various aspects of complement function.
• C3a is an anaphylatoxin (see discussion below).
• C3b binds to bacterial and other cells, as well as to certain viruses and immune complexes, and tags them for removal from the circulation. (C3b in this role is known as opsonin.)
• the opsonic function of C3b is generally considered to be the most important anti-infective action of the complement system. Patients with genetic lesions that block C3b function are prone to infection by a broad variety of pathogenic organisms, while patients with lesions later in the complement cascade sequence, i.e., patients with lesions that block C5 functions, are found to be more prone only to Neisseria infection, and then only somewhat more prone (Fearon, in Intensive Review of Internal Medicine, 2 nd Ed. Fanta and Minaker, eds. Brigham and Women's and Beth Israel Hospitals, 1983).
• C3b also forms a complex with other components unique to each pathway to form classical or alternative C5 convertase, which cleaves C5 into C5a and C5b.
• C3 is thus regarded as the central protein in the complement reaction sequence since it is essential to both the alternative and classical pathways (Wurzner, et al., Complement Inflamm. 8:328-340, 1991).
• This property of C3b is regulated by the serum protease Factor I, which acts on C3b to produce iC3b. While still functional as opsonin, iC3b cannot form an active C5 convertase.
• C5a is another anaphylatoxin (see discussion below).
• C5b combines with C6,
• the membrane attack complex (MAC, C5b-9, terminal complement complex--TCC) is formed.
• MAC membrane attack complex
• C5b-9 terminal complement complex--TCC
• MAC pores mediate rapid osmotic lysis of the target cells.
• non-lytic concentrations of MACs can produce other effects.
• membrane insertion of small numbers of the C5b-9 complexes into endothelial cells and platelets can cause deleterious cell activation. In some cases activation may precede cell lysis.
• C3a and C5a are anaphylatoxins. These activated complement components can trigger mast cell degranulation, which releases histamine and other mediators of inflammation, resulting in smooth muscle contraction, increased vascular permeability, leukocyte activation, and other inflammatory phenomena including cellular proliferation resulting in hypercellularity.
• C5a also functions as a chemotactic peptide that serves to attract pro-inflammatory granulocytes to the site of complement activation.
• any compounds which bind to or otherwise block the generation and/or activity of any of the human complement components are useful herein.
• Some compounds include 1) antibodies directed against complement components C-1 , C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, Factor D, Factor B, Factor P, MBL, MASP-1 , AND MASP-2 and 2) naturally occurring or soluble forms of complement inhibitory compounds such as CR1 , LEX- CR1, MCP, DAF, CD59, Factor H, cobra venom factor, FUT-175, y bind protein, complestatin, and K76 COOH.
• Suitable compounds for use herein are antibodies that reduce, directly or indirectly, the conversion of complement component C5 into complement components C5a and C5b.
• One class of useful antibodies are those having at least one antibody-antigen binding site and exhibiting specific binding to human complement component C5, wherein the specific binding is targeted to the alpha chain of human complement component C5.
• Such an antibody 1) inhibits complement activation in a human body fluid; 2) inhibits the binding of purified human complement component C5 to either human complement component C3 or human complement component C4; and 3) does not specifically bind to the human complement activation product for C5a.
• Particularly useful complement inhibitors are compounds which reduce the generation of C5a and/or C5b-9 by greater than about 30%.
• a particularly useful anti-C5 antibody is h5G1.1-scFv. Methods for the preparation of h5G1.1-scFv are described in U.S. Patent Application No. 08/487,283 filed June 7, 1995 now U.S. patent no. and "Inhibition of Complement
• CABG coronary-artery bypass graft
• CPB cardiopulmonary bypass
• CK-MB measurements For purposes of CK-MB measurements, intra- and post-operative blood draws were performed at 4, 8,16, 20, 24, 30 and 36 hours post-CPB. Additionally, the post operative day (POD) 2 CK-MB draw was at 48 hours post-CPB. There was a 30 minute window for each of these blood draws except for those drawn in the OR, which were exact. The POD 4 CK-MB draw was collected with routine blood draws. Measurements of CK-MB were made using a microparticle enzyme immunoassay that is commercially available under the tradename AxSYM system from Abbott Laboratories, (Abbott Park, Illinois).
• endpoints in CABG clinical trials have been discovered. Specifically, by using the methods disclosed herein endpoints in CABG trials with myocardial infarction defined, in part, by CK-MB peak levels of >50, >60, >70, >80, >90, >100 or >120 can be effectively utilized to evaluate anti-inflammatory drugs.
• this disclosure contemplates a method of prophylaxis against myocardial infarctions which exhibit CK- MB levels greater than about 50 nano-grams/ml in a subject.
• This method includes administering to the subject undergoing a procedure which involves CPB an effective myocardial infarction reducing amount of an anti-inflammatory compound. Ascertaining what amount constitutes an effective myocardial infarction reducing amount of the anti- inflammatory compound can be ascertained using the novel screening procedure described hereinabove, or by any technique known to those skilled in the art.
• the dosage of the anti-inflammatory compound that constitutes an effective myocardial infarction reducing amount will depend on a number of factors, including, for example, the specific anti-inflammatory compound selected and its method of operation. However, typically the anti-inflammatory compound can be administered in an amount ranging from about 0.01 mg/kg to about 20.0mg/kg, preferably from about 0.10mg/kg to about 10.0mg/kg. Any anti-inflammatory compound evaluated using the methods herein and determined to reduce the incidence of myocardial infarctions may be used in the present method of prophylaxis. Any compounds which bind to or otherwise block the generation and/or activity of any of the human complement components, such as, for example, antibodies specific to a human complement component are useful for prophylaxis.
• Some compounds include 1) antibodies directed against complement components C-1 , C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, Factor D, Factor B, Factor P, MBL, MASP-1 , AND MASP-2 and 2) naturally occurring or soluble forms of complement inhibitory compounds such as CR1, LEX-CR1, MCP, DAF, CD59, Factor H, cobra venom factor, FUT-175, y bind protein, complestatin, and K76 COOH, Suitable compounds for use herein are antibodies that reduce, directly or indirectly, the conversion of complement component C5 into complement components C5a and C5b.
• One class of useful antibodies are those having at least one antibody-antigen binding site and exhibiting specific binding to human complement component C5, wherein the specific binding is targeted to the alpha chain of human complement component C5.
• Such an antibody 1) inhibits complement activation in a human body fluid; 2) inhibits the binding of purified human complement component C5 to either human complement component C3 or human complement component C4; and 3) does not specifically bind to the human complement activation product for C5a.
• a particularly useful anti-C5 antibody is h5G1.1-scFv.

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