News Column

Patent Application Titled "Cancer Treatements" Published Online

July 18, 2014



By a News Reporter-Staff News Editor at Drug Week -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Markovic, Svetomir N. (Rochester, MN); Nevala, Wendy K. (Rochester, MN), filed on May 9, 2012, was made available online on July 3, 2014 (see also Mayo Foundation For Medical Education And Research).

The assignee for this patent application is Mayo Foundation For Medical Education And Research.

Reporters obtained the following quote from the background information supplied by the inventors: "This document relates to methods and materials involved in treating cancer (e.g., skin cancers such as melanoma). For example, this document relates to methods and materials involved in using complexes containing albumin-containing nanoparticles (e.g., Abraxane.RTM. nanoparticles) and antibodies (e.g., anti-VEGF polypeptide antibodies such as Avastin.RTM.) to treat cancer. This document also relates to methods and materials involved in using Abraxane.RTM. in combination with an anti-VEGF polypeptide antibody (e.g., Avastin.RTM.) to treat skin cancer.

"Melanoma is the most serious form of skin cancer. It is a malignant tumor that originates in melanocytes, the cells which produce the pigment melanin that colors skin, hair, and eyes and is heavily concentrated in most moles. While it is not the most common type of skin cancer, melanoma underlies the majority of skin cancer-related deaths. About 48,000 deaths worldwide are registered annually as being due to malignant melanoma. Worldwide, there are about 160,000 new cases of melanoma each year. Melanoma is more frequent in white men and is particularly common in white populations living in sunny climates. Other risk factors for developing melanoma include a history of sunburn, excessive sun exposure, living in a sunny climate or at high altitude, having many moles or large moles, and a family or personal history of skin cancer. Melanomas fall into four major categories. Superficial spreading melanoma can travel along the top layer of the skin before penetrating more deeply. Lentigo maligna typically appears as a flat or mildly elevated mottled tan, brown, or dark brown discoloration and is found most often in the elderly. Nodular melanoma can occur anywhere on the body as a dark, protuberant papule or a plaque that varies from pearl to gray to black. Acral-lentiginous melanoma, although uncommon, is the most common form of melanoma in blacks. It can arise on palmar, plantar, or subungual skin. Metastasis of melanoma occurs via lymphatics and blood vessels. Local metastasis results in the formation of nearby satellite papules or nodules that may or may not be pigmented. Direct metastasis to skin or internal organs can occur."

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "This document provides methods and materials involved in treating cancer (e.g., skin cancers such as melanoma). For example, this document provides methods and materials for using complexes containing albumin-containing nanoparticles (e.g., Abraxane.RTM. nanoparticles) and antibodies (e.g., anti-VEGF polypeptide antibodies such as Avastin.RTM.) to treat cancer. This document also provides methods and materials involved in using Abraxane.RTM. in combination with an anti-VEGF polypeptide antibody (e.g., Avastin.RTM.) to treat skin cancer (e.g., melanoma). Abraxane.RTM. is available from Celgene Corp. and is a nanoparticle formulation that combines paclitaxel with human albumin. Avastin.RTM. is also known as bevacizumab and is available from Genentech Corp. and Roche Corp. Avastin.RTM. is a humanized monoclonal antibody that binds to vascular endothelial growth factor A. As described herein, in vitro mixing of albumin-containing nanoparticles (e.g., Abraxane.RTM. nanoparticles) and antibodies (e.g., bevacizumab, bevacizumab, trastuzamab, or rituxan) can result in the formation of macromolecular complexes, the characteristics of which (e.g., size, antibody content, or chemotherapeutic drug content) can be customized depending on need. In some cases, such macromolecular complexes can retain antibody mediated target binding specificity, can retain or exhibit enhanced chemotherapeutic tumor cell cytotoxicity, and can exhibit no additional toxicity beyond that of Abraxane.RTM. nanoparticles alone. As also described herein, contacting Abraxane.RTM. with an anti-VEGF polypeptide antibody (e.g., Avastin.RTM.) prior to administration to a human (e.g., a human melanoma cancer patient) can result in a complex that, when administered as a complex, has an increased ability to treat melanoma as compared to a treatment regimen that includes administering Abraxane.RTM. and the anti-VEGF polypeptide antibody separately in a manner that does not form Abraxane.RTM./anti-VEGF polypeptide antibody complexes.

"The methods and materials provided herein can be used to increase the progression-free survival rate in skin cancer patients. Increasing progression-free survival can allow skin cancer patients to live longer.

"In general, one aspect of this document features a method for treating a mammal having skin cancer. The method comprises, or consists essentially of, administering to the mammal a composition containing Abraxane.RTM./anti-VEGF polypeptide antibody complexes (or complexes of (a) an anti-VEGF polypeptide antibody and (b) human albumin-containing nanoparticles having an agent other than placitaxel) under conditions wherein the length of progression-free survival is increased. The mammal can be a human. The skin cancer can be melanoma. The skin cancer can be stage IV melanoma. In some cases, a composition comprising Abraxane.RTM./Avastin.RTM. complexes can be administered to the mammal. The composition can comprise an alkylating agent. The alkylating agent can be a platinum compound. The platinum compound can be carboplatin. The anti-VEGF polypeptide antibody can be a humanized antibody. The anti-VEGF polypeptide antibody can be bevacizumab. The composition can be administered by injection. The progression-free survival can be increased by 25 percent. The progression-free survival can be increased by 50 percent. The progression-free survival is increased by 75 percent. The progression-free survival can be increased by 100 percent. The composition can be administered under conditions wherein the time to progression is increased.

"In another aspect, this document features a method for treating a mammal having cancer. The method comprises, or consists essentially of, administering, to the mammal, a composition comprising albumin-containing nanoparticle/antibody complexes, wherein the average diameter of the complexes is greater than 1 .mu.m (e.g., between 1.1 .mu.m and 5 .mu.m, between 1.5 .mu.m and 5 .mu.m, between 4.5 and 20 .mu.m, or between 5 and 20 .mu.m). The mammal can be a human. The cancer can be skin cancer. The skin cancer can be melanoma. The skin cancer can be stage IV melanoma. The albumin-containing nanoparticle/antibody complexes can be Abraxane.RTM./Avastin.RTM. complexes. The composition or the albumin-containing nanoparticle/antibody complexes can comprise an alkylating agent. The alkylating agent can be a platinum compound. The platinum compound can be carboplatin. The antibodies of the albumin-containing nanoparticle/antibody complexes can be anti-VEGF polypeptide antibodies. The anti-VEGF polypeptide antibodies can be humanized antibodies. The anti-VEGF polypeptide antibodies can be bevacizumab. The composition can be administered by injection. The administration of the composition can be effective to increase progression-free survival by 25 percent. The administration of the composition can be effective to increase progression-free survival by 50 percent. The administration of the composition can be effective to increase progression-free survival by 75 percent. The administration of the composition can be effective to increase progression-free survival by 100 percent. The administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the cancer is at least 150 days. The administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the cancer is at least 165 days. The administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the cancer is at least 170 days. The average diameter of the complexes can be from 1.1 .mu.m to 5 .mu.m. The average diameter of the complexes can be from 2 .mu.m to 5 .mu.m. The average diameter of the complexes can be from 3 .mu.m to 5 .mu.m. The average diameter of the complexes can be from 5 .mu.m to 50 .mu.m. The average diameter of the complexes can be from 10 .mu.m to 50 .mu.m. The average diameter of the complexes can be from 5 .mu.m to 25 .mu.m.

"In another aspect, this document features a method for treating a mammal having cancer. The method comprises, or consists essentially of, administering, to the mammal, a composition comprising albumin-containing nanoparticle/antibody complexes, wherein the average diameter of at least 5 percent of the complexes of the composition is greater than 1 .mu.m. The mammal can be a human. The cancer can be skin cancer. The skin cancer can be melanoma. The skin cancer can be stage IV melanoma. The albumin-containing nanoparticle/antibody complexes can be Abraxane.RTM./Avastin.RTM. complexes. The composition or the albumin-containing nanoparticle/antibody complexes can comprise an alkylating agent. The alkylating agent can be a platinum compound. The platinum compound can be carboplatin. The antibodies of the albumin-containing nanoparticle/antibody complexes can be anti-VEGF polypeptide antibodies. The anti-VEGF polypeptide antibodies can be humanized antibodies. The anti-VEGF polypeptide antibodies can be bevacizumab. The composition can be administered by injection. The administration of the composition can be effective to increase progression-free survival by 25 percent. The administration of the composition can be effective to increase progression-free survival by 50 percent. The administration of the composition can be effective to increase progression-free survival by 75 percent. The administration of the composition can be effective to increase progression-free survival by 100 percent. The administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the cancer is at least 150 days. The administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the cancer is at least 165 days. The administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the cancer is at least 170 days. The average diameter of at least 5 percent of said complexes of said composition can be from 1.1 .mu.m to 5 .mu.m. The average diameter of at least 5 percent of said complexes of said composition can be from 2 .mu.m to 5 .mu.m. The average diameter of at least 5 percent of said complexes of said composition can be from 3 .mu.m to 5 .mu.m. The average diameter of at least 5 percent of said complexes of said composition can be from 5 .mu.m to 50 .mu.m. The average diameter of at least 5 percent of said complexes of said composition can be from 10 .mu.m to 50 .mu.m. The average diameter of at least 5 percent of said complexes of said composition can be from 5 .mu.m to 25 .mu.m. The average diameter of at least 10 percent of said complexes of said composition can be greater than 1 .mu.m. The average diameter of at least 50 percent of said complexes of said composition can be greater than 1 .mu.m. The average diameter of at least 75 percent of said complexes of said composition can be greater than 1 .mu.m. The average diameter of at least 90 percent of said complexes of said composition can be greater than 1 .mu.m.

"Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

"The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

"FIG. 1 is a diagram of an Abraxane.RTM. nanoparticle (labeled A) complexed with an anti-VEGF polypeptide antibody (bevacizumab; labeled B). In two of the three cases, the anti-VEGF polypeptide antibody is shown binding to a VEGF-A polypeptide (labeled V), and a fluorescently-labeled anti-VEGF antibody (labeled aV*) is shown bound to the VEGF-A polypeptide.

"FIG. 2 contains scatter plots of a flow cytometry analysis plotting the level of yellow fluorescence of A alone, A plus aV*, A plus B plus aV*, A plus V plus aV*, or A plus B plus V plus aV*. The labels are as indicated in FIG. 1. These results demonstrate that A and B spontaneously associate and preserve a VEGF polypeptide binding potential.

"FIG. 3 is graph that contains the flow cytometry data from FIG. 2.

"FIG. 4 is a repeat of the experiment of FIG. 3, comparing A alone, A plus aV*, A plus B plus aV*, A plus V plus aV*, or A plus B plus V plus aV*. One difference is in FIG. 3, 500 ng of VEGF was used. In FIG. 4, 100 ng VEGF was used to visualize the complex.

"FIG. 5 is a graph plotting flow cytometry data of A plus B incubated in the presence of various concentrations of human plasma (1:1 to 1:16) followed by addition of V and aV*. These results indicate that human plasma diluted in a range of relative volumes (1:1 to 1:16) successfully inhibited the formation of the A+B complex relative to controls.

"FIG. 6 is a graph plotting flow cytometry data of A plus B incubated in the presence of various concentrations of human serum albumin (500 .mu.g, 50 .mu.g, 5 .mu.g, 0.5 .mu.g, and 0.05 .mu.g/mL) followed by addition of V and aV*. These results indicate that incubation with serum albumin (concentrations ranging from 500 .mu.g/mL to 0.05 .mu.g/mL) did not affect the complexing of A and B.

"FIG. 7 is a graph plotting flow cytometry data of A plus B incubated in the presence of various concentrations of human polyclonal immunoglobulin (500 .mu.g, 50 .mu.g, 5 .mu.g, 0.5 .mu.g, and 0.05 .mu.g/mL) followed by addition of V and aV*. These results indicate that incubation of A and B with a range of concentrations of human immunoglobulin (IVIG; 500 .mu.g/mL to 0.05 .mu.g/mL) partially inhibited A and B complexing.

"FIG. 8 contain A plus B complexing results in the presence of plasma (1:1), IVIG (0.5 mg/mL), or albumin (0.5 mg/mL). At the highest concentrations of plasma (1:1), IVIG (0.5 mg/mL), or albumin (0.5 mg/mL) tested, the levels of relative inhibition of A plus B complexing differ in diminishing order.

"FIG. 9 contains photographs of light microscope images of Abraxane.RTM. (ABX) or mixtures of Abraxane.RTM. (ABX) and bevacizumab (BEV; 0.5, 5, 10, or 25 mg/mL) either 4 or 24 hours after mixing.

"FIG. 10 is a graph plotting flow cytometry results of Abraxane.RTM. alone, ABX:BEV complexes, and 2 .mu.m standard beads.

"FIG. 11 is graph plotting the proliferation index for A375 cells (a melanoma tumor cell line) exposed to Abraxane.RTM. (ABX) only, Abraxane.RTM.:Herceptin (non-VEGF targeting) complexes, or Abraxane.RTM.:Bevacizumab (VEGF targeting) complexes at the indicated dose.

"FIG. 12 contains graphs plotting the percent BEV binding for ABX:BEV complexes exposed to 0.9% saline at room temperature or human plasma at 37.degree. C. for the indicated times.

"FIG. 13 contains a line graph plotting the proliferation index for A375 cells exposed to Abraxane.RTM. (ABX) only, cisplatin only, or Abraxane.RTM.:cisplatin complexes at the indicated dose and contains a bar graph plotting demonstrating that 30% of cisplatin (CDDP) remained unbound after ABX:cisplatin were mixed and incubated for 30 minutes.

"FIG. 14 contains scatter plots of a flow cytometry analysis of the indicated complexes containing Abraxane.RTM.

"FIG. 15 contains photographs of Western blot analyses of the indicated materials assessed for bevacizumab or taxol.

"FIG. 16 contains graphs of the size distributions of the indicated complexes incubated for the indicated time.

"FIG. 17 contains graphs of the size distributions of the indicated complexes incubated for one hour at room temperature.

"FIG. 18 is a photograph of a Western blot analysis of ABX:BEV complexes exposed to serum for 15, 30, 45, or 60 minutes. The ABX:BEV complexes were formed by incubating either 6 mg or 8 mg of BEV with ABX for 30 minutes at room temperature. The primary antibody used for the Western blot was an anti-paclitaxel antibody. Lane 1: ABX:BEV (6 mg) exposed to serum for 15 minutes; Lane 2: ABX:BEV (6 mg) exposed to serum for 30 minutes; Lane 3: ABX:BEV (6 mg) exposed to serum for 45 minutes; Lane 4: ABX:BEV (6 mg) exposed to serum for 60 minutes; Lane 5: blank; Lane 6: ABX:BEV (8 mg) exposed to serum for 15 minutes; Lane 7: ABX:BEV (8 mg) exposed to serum for 30 minutes; Lane 8: ABX:BEV (8 mg) exposed to serum for 45 minutes; Lane 9: ABX:BEV (8 mg) exposed to serum for 60 minutes.

"FIG. 19 is a photograph of a Western blot analysis of mixtures of paclitaxel (0.1, 0.5, 1, or 2 mg) and BEV (4 mg) incubated together for 30 minutes at room temperature. The primary antibody used for the Western blot was an anti-paclitaxel antibody. Lane 1: Bev (4 mg); Lane 2: Taxol (2 mg); Lane 3: Taxol (2 mg)+Bev (4 mg); Lane 4: Taxol (1 mg)+Bev (4 mg); Lane 5: Taxol (0.5 mg)+Bev (4 mg); Lane 6: Taxol (0.1 mg)+Bev (4 mg).

"FIG. 20 contains graphs plotting the particle size distribution for ABX:BEV complexes as determined using a Mastersizer 2000E (Malvern Instruments Ltd., Worcestershire, England). ABX (20 mg/mL) and BEV (16, 24, or 32 mg/mL) were incubated for 1, 2, or 4 hours at room temperature. After incubation, the mixtures were diluted 1:4 for a final concentration of ABX (5 mg/mL) and BEV (4, 6, or 8 mg/mL), and the diluted samples analyzed using a Mastersizer 2000E."

For more information, see this patent application: Markovic, Svetomir N.; Nevala, Wendy K. Cancer Treatements. Filed May 9, 2012 and posted July 3, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3552&p=72&f=G&l=50&d=PG01&S1=20140626.PD.&OS=PD/20140626&RS=PD/20140626

Keywords for this news article include: Antineoplastic Monoclonal Antibodies, Drugs, Avastin, Taxoids, Therapy, Terpenes, Cisplatin, Immunology, Paclitaxel, Bevacizumab, Hydrocarbons, Legal Issues, Nanoparticle, Blood Proteins, Cycloparaffins, Nanotechnology, Immunoglobulins, Protein Kinases, Alkylating Agents, Membrane Proteins, Chlorine Compounds.

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Source: Drug Week


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