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Caveolae Targeted Cisplatin Immunoconjugates for Effective Lung Cancer Therapy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA217399-01A1
Agency Tracking Number: R41CA217399
Amount: $299,999.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA16-303
Timeline
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-09-01
Award End Date (Contract End Date): 2019-02-28
Small Business Information
505 COAST BLVD S, STE 209, La Jolla, CA, 92037-4614
DUNS: 080202185
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 MICHAEL LEVIN
 (858) 229-1410
 mlevin@prism-sd.org
Business Contact
 L JEAN REMMER
Phone: (858) 450-9999
Email: jremmer@cavatar-sd.org
Research Institution
 PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
 505 COAST BOULEVARD SOUTH STE 209
LA JOLLA, CA, 92037-4614
 Domestic nonprofit research organization
Abstract
Abstract Caveolae at the endothelial cells surface can selectively rapidly and actively pump targeted antibodies out of the bloodstream and into underlying tissue in vivo even when they are conjugated to high molecular weight cargo Based on this exciting recent discovery we also found that caveolae pumping system enables unprecedented tumor specific targeting and penetration Taken together our evidence strongly supports that targeting tumor caveolae is a new strategy providing a portal to deliver therapeutic agents across the vascular endothelial cell barrier and directly into tumors Caveolae can rapidly pump a targeted antibody with the attached cargo across the endothelial cells to reach concentrations inside solid tumors that greatly exceed maximum concentrations in the blood In this project we will focus on testing of the therapeutic utility of the antibody cisplatin CMdextran immunoconjugates to target truncated form of Annexin A in tumor endothelial caveolae and to effectively penetrate solid tumors The data will provide proof of principle of our innovative delivery strategy for therapy of lung cancer and moves toward clinical translation by assessing how well caveolae immunotargeting and pumping into tumors can enhance the therapeutic impact of chemotherapy We will design synthesize and asses in vivo the efficacy of cisplatin carboxymethyl dextran CMdextran AnnA antibody conjugate to create new tumor caveolae targeted therapeutics for enhanced delivery and efficacy in lung cancer models using our advanced animal models We hypothesize that by pumping antibodies armed with cisplatin CMdextran into tumors caveolae can rapidly and specifically concentrate therapeutic agents inside tumors and enhance tumor destruction with significantly reduced toxicity The Specific Aims of this project are Aim to characterize in vivo delivery of cisplatin immunoconjugates targeting EC caveolae in tumors and Aim to assess therapeutic efficacy of the EC caveolae targeting cisplatin immunoconjugates This project will utilize our new intravital microscopy IVM tumor model system in addition to spontaneous mammary tumors from genetically engineered mice IVM permits direct visualization of targeting and endothelial processing as well as stroma and tumor cell responses all of which can be quantified to help provide new insights into therapeutic mechanisms in tumors Targeting caveolae opens a specific gateway across the restrictive vascular endothelial barrier It can provide means for enhanced delivery much closer to ideal targeting in order to achieve more effective therapies We have demonstrated that AnnA is expressed in the vasculature and caveolae of human primary and metastatic lung tumors Overall our proposed project could create a paradigm shift away from the passive transvascular delivery that greatly limits drug efficacy in humans affording the first prototype of caveolae targeted anticancer therapeutics for future translation into the clinic Public Health Relevance Statement Every year more than new lung cancer cases are reported in the United States and more than patients will die from this disease Despite the high incidence and mortality rates current lung cancer therapies are still relying upon systemically administered chemotherapeutic drugs that reach every organ of the patientandapos s body Unfortunately due to the limited permeability of the vascular walls only a small fraction of the intravenously administered dose actually reaches tumors This requires continuously increasing doses of the chemotherapeutic drugs in order to achieve at least some level of therapeutic efficacy and is often leading to multiple adverse side effects and drastically reduces quality of life of lung cancer patients Thus the efficacy of many systemically administered breast cancer therapies is seriously compromised by the significant barriers that inhibit drug delivery The overall objective of this study is to use our newly discovered mechanism the caveolae pumping system in order to provide an effective solution to the cisplatin delivery and toxicity problems for patients with lung cancer We discovered the unique mechanism for therapeutics to traverse the blood vessel barrier and designed a strategy that could significantly enhance therapeutic effectiveness while decreasing toxicity of anticancer therapeutics With support of this grant application we plan to produce antibody cisplatin immunoconjugates the hitherto unknown drug candidates with high therapeutic efficacies and greatly reduced systemic toxicity ultimately offering delivery platform for safe effective lung cancer therapy

* Information listed above is at the time of submission. *

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