Compounds and methods for modulating pharmacokinetics

Abstract

Methods and compositions are described for management of the pharmacokinetic properties of active agents, e.g., therapeutic moieties, by conjugating, fusing, or non-direct linkage of the active agent to one or more wild-type or modified heparin-binding peptides (HB). Compounds may be administered to tissues including skin. Contemplated uses include treatment of disease, allergen immunotherapy, and immunization. Other aspects relate to compositions, methods and kits comprising heparin-binding peptides (HB) fused or conjugated to the therapeutic agents.

What is claimed is: 
     
         1 . A composition for controlled systemic release of a therapeutic, the composition comprising:
 a therapeutic moiety; and   at least one heparin binding peptide linked to the therapeutic moiety, wherein the heparin binding peptide includes a portion with a sequence differing from KRKKKGKGLGKKRDPCLRKYK (SEQ ID NO: 1) by at least one amino acid.   
     
     
         2 . The composition of  claim 1  wherein the sequence shares at least 80% amino acid identity with KRKKKGKGLGKKRDPCLRKYK. 
     
     
         3 . The composition of  claim 2  wherein the sequence shares at least 95% amino acid identity with KRKKKGKGLGKKRDPCLRKYK. 
     
     
         4 . The composition of  claim 3 , further comprising at least a second heparin binding peptide comprising a sequence sharing at least 80% amino acid identity with KRKKKGKGLGKKRDPCLRKYK. 
     
     
         5 . The composition of  claim 1  wherein the sequence is KRKKKGKGLGKKRDPCLRKYK except that the C at the 16 th  position has been replaced by the at least one amino acid. 
     
     
         6 . The composition of  claim 5  wherein the sequence is one selected from the group consisting of: KRKKKGKGLGKKRDPRLRKYK (SEQ ID NO: 2); and KRKKKGKGLGKKRDPKLRKYK (SEQ ID NO: 3). 
     
     
         7 . The composition of  claim 5  wherein the sequence is KRKKKGKGLGKKRDPSLRKYK (SEQ ID NO: 82). 
     
     
         8 . The composition of  claim 1  wherein the therapeutic moiety comprises insulin-like growth factor 1 (IGF-1) or Interleukin 1 receptor antagonist (IL-IRA). 
     
     
         9 . The composition of  claim 1 , further comprising one or more of a polyhistidine tag, a FLAG-tag, and a hydrogel. 
     
     
         10 . The composition of  claim 1 , wherein the composition is produced through  E. coli  expression. 
     
     
         11 . The composition of  claim 1 , wherein the therapeutic moiety comprises a Neurotrophic factor. 
     
     
         12 . The composition of  claim 11 , wherein the Neurotrophic factor is selected from the group consisting of neurotrophins, glial cell-line derived neurotrophic factor family ligands, and neuropoietic cytokines. 
     
     
         13 . The composition of  claim 1 , wherein the therapeutic moiety comprises a therapeutic antibody or portion thereof. 
     
     
         14 . A composition for increasing retention of a therapeutic in tissue, the composition comprising:
 a therapeutic moiety; and   at least one heparin binding peptide linked to the therapeutic moiety, wherein the heparin binding peptide includes a portion with a sequence differing from KRKKKGKGLGKKRDPCLRKYK (SEQ ID NO: 1) by at least one amino acid.   
     
     
         15 . The composition of  claim 14  wherein the sequence shares at least 80% amino acid identity with KRKKKGKGLGKKRDPCLRKYK. 
     
     
         16 . The composition of  claim 15  wherein the sequence shares at least 95% amino acid identity with KRKKKGKGLGKKRDPCLRKYK. 
     
     
         17 . The composition of  claim 16 , further comprising at least a second heparin binding peptide comprising a sequence sharing at least 80% amino acid identity with KRKKKGKGLGKKRDPCLRKYK. 
     
     
         18 . The composition of  claim 14 , wherein the sequence is KRKKKGKGLGKKRDPCLRKYK except that the C at the 16 th  position has been replaced by the at least one amino acid. 
     
     
         19 . The composition of  claim 18 , wherein the sequence is one selected from the group consisting of: KRKKKGKGLGKKRDPRLRKYK (SEQ ID NO: 2); and KRKKKGKGLGKKRDPKLRKYK (SEQ ID NO: 3). 
     
     
         20 . The composition of  claim 18 , wherein the sequence is KRKKKGKGLGKKRDPSLRKYK (SEQ ID NO: 82). 
     
     
         21 . The composition of  claim 14 , wherein the therapeutic moiety comprises an immunomodulator. 
     
     
         22 . The composition of  claim 21 , wherein the immunomodulator comprises an agent that stimulates an immune response. 
     
     
         23 . The composition of  claim 22 , wherein the agent stimulates, in a patient, an immune response to prevent or treat a disease selected from the group consisting of anthrax, botulism, measles, rubella, cholera, meningococcal disease, influenza, diphtheria, mumps, tetanus, hepatitis A, pertussis, tuberculosis, hepatitis B, hepatitis C, pneumococcal disease, streptococcal disease, staphylococcal disease, typhoid fever, dengue, hepatitis E, poliomyelitis, hand-foot-mouth disease, tick-born encephalitis,  Haemophilus influenzae  meningitis, rabies, varicella and herpes zoster (shingles), human papilloma-virus infection, rotavirus gastroenteritis, yellow fever, Japanese encephalitis, West Nile fever, filoviral hemorrhagic fever, human immunodeficiency virus infection, malaria, and chikungunya 
     
     
         24 . The composition of  claim 22 , wherein the agent comprises a vaccine. 
     
     
         25 . The composition of  claim 21 , wherein the immunomodulator comprises an agent that inhibits an immune response. 
     
     
         26 . The composition of  claim 25 , wherein the agent comprises an allergen. 
     
     
         27 . The composition of  claim 26 , wherein the allergen is adapted to induce tolerance in a patient to one selected from the group consisting of pollen, pet dander, dust mites, airborne molds, tree nuts, peanuts, fruits, milk, eggs, fish, shellfish, honey bee venom, yellow jacket venom, hornet venom, wasp venom, and fire ant venom. 
     
     
         28 . The composition of  claim 21 , wherein the immunomodulator comprises an agent that inhibits an immunologic response in a patient with an autoimmune disease. 
     
     
         29 . The composition of  claim 21 , wherein the immunomodulator comprises an agent that inhibits an inflammatory response in a patient with an autoimmune disease. 
     
     
         30 . A method of treating a patient, the method comprising:
 administering a compound to a location within the skin of a patient, wherein the compound comprises at least one heparin binding peptide and a therapeutic moiety, wherein the heparin binding peptide modifies the pharmacokinetic properties of the therapeutic moiety within skin relative to the therapeutic moiety alone.   
     
     
         31 . The method of  claim 30 , wherein the compound comprises a plurality of heparin binding peptides to elicit a desired release profile for the compound. 
     
     
         32 . The method of  claim 30 , wherein the administering step comprises one selected from the list consisting of: intradermal injection, subcutaneous injection, and transdermal delivery. 
     
     
         33 . The method of  claim 30 , wherein the therapeutic moiety comprises an immunomodulator. 
     
     
         34 . The method of  claim 33 , wherein the immunomodulator comprises an agent that stimulates an immune response. 
     
     
         35 . The method of  claim 34 , wherein the agent stimulates, in the patient, an immune response to prevent or treat a disease selected from the group consisting of anthrax, botulism, measles, rubella, cholera, meningococcal disease, influenza, diphtheria, mumps, tetanus, hepatitis A, pertussis, tuberculosis, hepatitis B, hepatitis C, pneumococcal disease, streptococcal disease, staphylococcal disease, typhoid fever, dengue, hepatitis E, poliomyelitis, hand-foot-mouth disease, tick-born encephalitis,  Haemophilus influenzae  meningitis, rabies, varicella and herpes zoster (shingles), human papilloma-virus infection, rotavirus gastroenteritis, yellow fever, Japanese encephalitis, West Nile fever, filoviral hemorrhagic fever, human immunodeficiency virus infection, malaria, and chikungunya. 
     
     
         36 . The method of  claim 34 , wherein the agent comprises a vaccine. 
     
     
         37 . The method of  claim 33 , wherein the immunomodulator comprises an agent that inhibits an immune response. 
     
     
         38 . The method of  claim 37 , wherein the agent comprises an allergen. 
     
     
         39 . The method of  claim 38 , wherein the allergen is adapted to induce tolerance in a patient to one selected from the group consisting of pollen, pet dander, dust mites, airborne molds, tree nuts, peanuts, fruits, milk, eggs, fish, shellfish, honey bee venom, yellow jacket venom, hornet venom, wasp venom, and fire ant venom. 
     
     
         40 . The method of  claim 30 , wherein the therapeutic moiety comprises a Neurotrophic factor. 
     
     
         41 . The method of  claim 40 , wherein the Neurotrophic factor is selected from the group consisting of neurotrophins, glial cell-line derived neurotrophic factor family ligands, and neuropoietic cytokines. 
     
     
         42 . The method of  claim 30 , wherein the therapeutic moiety is a therapeutic antibody or portion thereof. 
     
     
         43 . The method of  claim 30 , wherein the therapeutic moiety comprises insulin-like growth factor 1 (IGF-1) or Interleukin 1 receptor antagonist (IL-IRA). 
     
     
         44 . The method of  claim 30 , wherein the compound further comprises a hydrogel. 
     
     
         45 . The method of  claim 30 , wherein the therapeutic moiety comprises one selected from the group consisting of a hemophiliac inhibitor, factor VIII (fVIII), a Trk kinase inhibitor, C Natriuretic peptide, Kartigenin, and Trofinetide