Boroproline compound combination therapy

• US 20050084490A1
• Filed: 07/09/2003
• Published: 04/21/2005
• Est. Priority Date: 07/09/2002
• Status: Abandoned Application

• Current Assignee: Point Therapeutics, Inc. (Barings LLC (Private Equity))
• Original Assignee: Point Therapeutics, Inc. (Barings LLC (Private Equity))
• Inventors: Jones, Barry, Adams, Sharlene, Miller, Glenn T., Jesson, Michael I.
• Application Number:
  US10/616,409
• Publication Number:
  US 20050084490A1
• Time in Patent Office: Days
• US Class Current: 424/144.100
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/04 Amoebicides
• CPC Class Codes: A61P 33/10 : Anthelmintics
• CPC Class Codes: A61P 33/12 : Schistosomicides
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A method is provided for treating subjects with combination therapy including compounds of Formula I. It was surprisingly discovered that this combination enhanced the efficacy of both agents, and that administration of Formula I compounds induced cytokine and chemokine production in vivo. The combinations can be used to enhance ADCC, stimulate immune responses and/or patient and treat certain disorders. The invention also relates to kits and compositions relating to such combinations.

Claims

1. A method for stimulating an immune response in a subject comprising administering to a subject in need of immune stimulation an agent of Formula I, and an antibody or antibody fragment, in an amount effective to stimulate an immune response.

2. The method of claim 1, wherein the immune response is antibody dependent cell-mediated cytoxicity.

3. The method of claim 1, wherein the antibody or antibody fragment is an antibody.

4. The method of claim 1, wherein the antibody or antibody fragment is an anti-HER2 antibody.

5. The method of claim 4, wherein the anti-HER2 antibody is trastuzumab.

6. The method of claim 1, wherein the antibody or antibody fragment is an anti-CD20 antibody.

7. The method of claim 6, wherein the anti-CD20 antibody is rituximab.

8. The method of claim 1, wherein the antibody or antibody fragment is administered in a sub-therapeutic dose.

9. The method of claim 1, wherein the agent of Formula I is administered in a route of administration different from that of the antibody or antibody fragment.

10. The method of claim 1, wherein the agent of Formula I is administered orally and the antibody or antibody fragment is administered by injection.

11. The method of claim 1, wherein the agent of Formula I is administered prior to the antibody or antibody fragment.

12. The method of claim 11, wherein the agent of Formula I is administered 30 minutes to 8 hours prior to the antibody or antibody fragment.

13. The method of claim 11, wherein the agent of Formula I is administered 1 to 7 days prior to the antibody or antibody fragment.

14. The method of claim 1, wherein the agent of Formula I is administered substantially simultaneously with the antibody or antibody fragment.

15. The method of claim 1, wherein the agent of Formula I is administered after the antibody or antibody fragment.

16. The method of claim 15, wherein the agent of Formula I is administered 30 minutes to 8 hours after the antibody or antibody fragment.

17. The method of claim 15, wherein the agent of Formula I is administered 1 to 7 days after the antibody or antibody fragment.

25. The method of claim 1, wherein the subject is a subject having or at risk of developing cancer.

30. The method of claim 1, wherein the subject is a subject having or at risk of developing an infectious disease.

139. The method of claim 1, wherein the antibody or antibody fragment is administered on a first day of a seven day cycle and the agent of Formula I is administered twice a day on day two through day seven.

142. The method of claim 1, wherein the antibody or antibody fragment is conjugated to a toxin derived from plant, fungus, or bacteria.

144. The method of claim 1, wherein the antibody or antibody fragment is conjugated to a chemotherapeutic agent or a radioisotope.

166. The method of claim 1, wherein the antibody or antibody fragment is selected from the group consisting of Avastin (bevacizumab), BEC2 (mitumomab), Bexxar (tositumomab), Campath (alemtuzumab), CeaVac, Herceptin (trastuzumab), IMC-C225 (centuximab), LymphoCide (epratuzumab), MDX-210, Mylotarg (gemtuzumab ozogamicin), Panorex (edrecolomab), Rituxan (rituximab), Theragyn (pemtumomab), Zamyl, and Zevalin (ibritumomab tituxetan).

251. The method of claim 1, wherein the agent of Formula I is an agent of Formula II.

252. The method of claim 1, wherein the agent of Formula I is an agent of Formula III.

253. The method of claim 1, wherein the agent of Formula I is selected from the group consisting of L-Val-L-boroPro, L-Met-L-boroPro, and L-Ile-L-boroPro.

254. The method of claim 1, wherein the agent of Formula I is in a cyclic form.

255. The method of claim 1, wherein the agent of Formula I is administered in an amount that increases lymphoid tissue levels of IL-1, G-CSF or IL-8.

256. The method of claim 1, wherein the agent of Formula I is administered in an amount that does not increase serum IL-1 levels.

257. The method of claim 1, wherein the IL-1 is IL-1α

or IL-1β

.

258. The method of claim 1, wherein the subject is otherwise free of symptoms calling for hematopoietic stimulation.

259. The method of claim 1, wherein the agent of Formula I is administered on a routine schedule.

260. The method of claim 1, wherein the subject is HIV negative.

338. The method of claim 1, wherein the agent of Formula I is at least 96% pure L-isomer.

18. A method for stimulating an immune response in a subject having or at risk of having cancer comprising administering to a subject in need of immune stimulation an agent of Formula I, and an antigen, in an amount effective to stimulate an antigen-specific immune response.

19-23. -23. (canceled)

24. A method for stimulating an immune response in a subject comprising administering to a subject in need of immune stimulation an agent of Formula I, and an antigen, in an amount effective to stimulate an antigen-specific immune response, wherein the agent of Formula I is administered at a concentration of greater than 10⁻

8M.

26-29. -29. (canceled)

31-80. -80. (canceled)

81. A method of preventing an infectious disease in a subject at risk of developing an infectious disease comprising

identifying a subject at risk of developing an infectious disease, and

administering an agent of Formula I to the subject in an amount effective to induce IL-1.

82-89. -89. (canceled)

90. A method for stimulating an immune response in a non-immunocompromised subject comprising

administering to a subject in need thereof an agent of Formula I, in an amount effective to induce IL-1.

91-96. -96. (canceled)

97. A method for stimulating an immune response in an immunocompromised subject comprising administering to a subject in need thereof an agent of Formula I, in an amount effective to induce IL-1.

98-138. -138. (canceled)

140-141. -141. (canceled)

143. (canceled)

145-165. -165. (canceled)

167. (canceled)

168. A method for treating a subject having or at risk of developing an IFN-responsive condition comprising

administering to a subject in need of such treatment an agent of Formula I in an amount effective to induce a therapeutically or prophylactically effective amount of IL-1 in the subject.

169-176. -176. (canceled)

177. A method for treating a subject having or at risk of developing cancer comprising administering to a subject in need of such treatment an enzyme inhibitor selected from the group consisting of a tyrosine kinase inhibitor, a CDK inhibitor, a MAP kinase inhibitor, and an EGFR inhibitor, and an agent of Formula I in an amount effective to inhibit the cancer.

178-181. -181. (canceled)

182. A method for treating a subject having or at risk of developing cardiovascular disease comprising

administering to a subject in need of such treatment an agent of Formula I in an amount effective to induce an effective amount of IL-1.

183. (canceled)

184. A method for preventing drug resistance in a subject having an infectious disease comprising

administering to a subject receiving an anti-microbial agent, an agent of Formula I in an amount effective to reduce the risk of resistance to the anti-microbial agent.

185-187. -187. (canceled)

188. A method of shortening a vaccination course comprising

administering to a subject in need of immunization an agent of Formula I in an amount effective to induce an antigen-specific immune response to a vaccine administered in a vaccination course,

wherein the vaccination course is shortened by at least one immunization.

189-190. -190. (canceled)

191. A method of shortening a vaccination course comprising

administering to a subject in need of immunization an agent of Formula I in an amount effective to induce an antigen-specific immune response to a vaccine administered in a vaccination course,

wherein the vaccination course is shortened by at least one day.

192-194. -194. (canceled)

195. A method for stimulating an immune response in a subject having cancer comprising

administering to a subject in need of such treatment an agent of Formula I in an amount effective to stimulate an antigen-specific immune response, prior to and following a therapy selected from the group consisting of radiation, surgery and chemotherapy.

196. (canceled)

197. A method for stimulating an immune response in a subject at risk of developing cancer comprising

administering to a subject in need of such treatment an agent of Formula I in an amount effective to stimulate an antigen-specific immune response.

198-209. -209. (canceled)

210. A method for modulating an immune response comprising

administering to a subject in need thereof an antibody or an antibody fragment on a first day of a seven day cycle, and administering to the subject an agent of Formula I on day 2 through to day 7 of the seven day cycle.

211-250. -250. (canceled)

261. A composition comprising

an effective amount of an agent of Formula I and an antibody or antibody fragment.

262-289. -289. (canceled)

290. A composition comprising

an effective amount of an agent of Formula I and a cancer antigen.

291-319. -319. (canceled)

320. A composition comprising

an effective amount of an agent of Formula I and a microbial antigen,

wherein the agent of Formula I is formulated for administration at a dose of greater than 10⁻

8M.

321-337. -337. (canceled)

339. (canceled)