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  Modified therapeutic agentsUSPTO Application #: 20060241048Title: Modified therapeutic agents Abstract: The invention provides a modified therapeutic agent, said modified agent comprising three or more membrane binding elements with low membrane affinity covalently associated with the agent which elements are capable of interacting independently and with thermodynamic additivity, with components of cellular or artificial membranes exposed to extracellular fluids wherein at least two membrane binding elements are lipophilic elements, which may be aliphatic acyl groups, which may be selected from the list consisting of Myristoyl, Decanoyl or Hexanoyl. (end of abstract) Agent: Proskauer Rose LLP - Washington, DC, US Inventors: Dirk Esser, Jason Richard Betley, Simon Hugh Ridley USPTO Applicaton #: 20060241048 - Class: 514013000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 16 To 24 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20060241048. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This invention relates to modified therapeutic agents, their use in therapy and intermediates. More particularly it relates to soluble therapeutic agents containing membrane binding elements. [0002] Many drugs are administered in a pharmaceutical solution with the drug dissolved in a physiological solution suitable for injection. Further, other drugs are administered in a dry form such as a tablet. In this form, the tablet dissolves after administration releasing the drug, which is absorbed into the bloodstream where it will be transported, by the blood, to its site of action. Whatever form the drug is administered in it is transported in soluble form within the bloodstream. [0003] Biotechnology has-increased the number of potential drugs that are proteins or protein based. Essentially all protein drugs are administered as solutions and function in vivo in the solution phase. In biochemistry and pharmacology, however, a large number of control and mediator proteins are associated with or function within or on the plasma membranes of cells. Except for soluble, truncated versions of one class of these molecules, no membrane-associated proteins have been developed as therapeutic agents. There are two main reasons for this situation. Firstly, overexpression of proteins that are retained in the membranes of the producer cells is limited by the low capacity of membranes for proteins and often by the toxic effects of retention when expression is intrinsically efficient. Secondly, extraction of these proteins from membranes requires detergents or organic solvents, often results in inactivation of the protein, leads to difficulties in achieving the high purity needed for drug use and usually gives a product which is hard to formulate for intravenous administration. [0004] Soluble, truncated versions of membrane-associated proteins overcome the production difficulties associated with full length proteins. However such truncated molecules lack the membrane binding capability and specificity of the full length proteins which properties may be advantageous or even essential to the desired therapeutic activity. In addition, the biological action of other chemically derived drugs may benefit from being targeted to or within close proximity to, a cellular membrane. [0005] WO 98/02454 describes a soluble derivative of a soluble polypeptide which comprises two or more heterologous membrane binding elements with low membrane affinity covalently associated with the polypeptide which elements are capable of interacting, independently and with thermodynamic additivity (Dill, K. A. J. Biol. Chem. 1997. 272, 701-704), with components of cellular or artificial membranes exposed to extracellular fluids ie. to the external surface of the cell or artificial membrane. [0006] By `heterologous` is meant that the elements are not found in the native full length protein from which a soluble protein may be derived. [0007] By `soluble polypeptide` is meant a truncated derivative of a full length protein which lacks its natural membrane binding capability, and/or a polypeptide which has a solubility level in aqueous media of >100 .mu.g/ml. [0008] By `membrane binding element with low membrane affinity` is meant that the element has a measurable but relatively low affinity for membranes, that is a dissociation constant greater than 1 .mu.M, preferably 1 .mu.M-1 mM. The elements preferably have a size <5 kDa. [0009] A modified therapeutic agent has sufficient membrane binding elements with low affinities for membrane components to result in a derivative with a high (preferably 0.01-10 nM dissociation constant) affinity for specific membranes. The elements combine so as to create an overall high affinity for the particular target membrane but the combination lacks such high affinity for other proteins for which single elements may be (low-affinity) ligands. [0010] The elements should be chosen so as to retain useful solubility in pharmaceutical formulation media, preferably >100 .mu.g/ml. [0011] Surprisingly, we have now found that an intermediate in the preparation of a modified therapeutic agent, namely three linked membrane binding elements, consisting of a basic amino acid element and two lipophilic elements remains soluble when prepared and isolated. [0012] When modifying a therapeutic agent, the membrane binding elements can be added sequentially, with the first conjugated to the therapeutic agent, then subsequent elements being conjugated to each other. A second method of modifying the agent is to prepare the membrane binding elements separately, conjugate the elements to each other first, isolate the whole and then conjugate the preparation to the therapeutic agent. [0013] When modifying peptides and proteins, the membrane binding element preparation (known as a "tail") is preferably soluble in aqueous solutions. This is to avoid the use of solvents to dissolve the tail prior to the conjugation to the peptide, which may damage the peptide. It is a surprising feature of the present invention that a tail with two lipophilic binding elements may be soluble in aqueous solution. [0014] Further, when this soluble tail was added to a therapeutic agent the resultant modified therapeutic agent remained soluble. [0015] In addition, it was found that a modified therapeutic agent containing this highly lipophilic tail had a lower affinity for serum albumin as compared to a therapeutic agent with only a single lipophilic membrane binding element. Under certain circumstances this reduced serum albumin affinity is preferable, potentially increasing the binding of the agent to cellular membranes. [0016] The present invention therefore provides a modified therapeutic agent, said agent comprising three or more membrane binding elements wherein at least two elements are lipophilic. [0017] The two lipophilic membrane binding elements may be different but preferably will be identical. [0018] The lipophilic membrane binding elements are preferably a C.sub.6-20 fatty acyl derivative of an amino C.sub.2-6 alkane thiol (optionally C-substituted) such as N-(2-myristoyl) aminoethanethiol or N-myristoyl L-cysteine. [0019] However, other elements will be known to those in the art. In general the lipophilic membrane binding element is defined as; [0020] having from 6 to 30, carbon atoms including those of any aromatic rings, if present; [0021] being straight or branched (for example having two or three branch points); [0022] saturated or unsaturated (for example containing one or more double or triple bonds); [0023] having one or more (such as 1, 2, 3 or 4) heteroatoms independently selected from S, O, or N; [0024] optionally, containing one or more, for example two or three aromatic rings, which may or may not be fused and each of which may contain from one or more (such as 1, 2, 3 or 4) heteratoms which, if present, are independently selected from N, O, or S and; Continue reading... Full patent description for Modified therapeutic agents Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Modified therapeutic agents 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 Modified therapeutic agents or other areas of interest. ### Previous Patent Application: Inhibiting furin with polybasic peptides Next Patent Application: Use of thrombin-derived peptides for the therapy of chronic dermal ulcers Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Modified therapeutic agents patent info. 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