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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
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
La Jolla, CA 92037-4614
United States
DUNS: 080202185
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (858) 229-1410
Business Contact
Phone: (858) 450-9999
Research Institution
LA JOLLA, CA 92037-4614
United States

 Domestic Nonprofit Research Organization

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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