My immediate career goal is continue my research in the fields of cancer research focusing mainly in the development of new drugs for cancer therapy. To achieve this goal I propose to develop universal delivery systems that can be used to deliver DNA or cytotoxic molecules to tumor cells expressing on their surface the interleukin-2 (IL-2) or transferrin (Tf) receptor (IL-2R or Tf-R). The delivery system will be antibody fusion proteins that either have the ligand (e.g., IL-2 or Tf) covalently associated or have a variable region that recognizes a growth factor receptor (e.g., anti-TfR). The antibody fusion proteins containing IL- 2 or Tf will be specific for the hapten dansyl (DNS) and will be used for the delivery of dansylated agents. The anti-TfR antibody will be covalently fused to avidin and will be used for the delivery of biotinylated agents. To produce and characterize the delivery vehicles I propose the following specific aims: 1. Produce the recombinant antibody fusion proteins to be used as universal delivery vehicles; 2. Evaluate the ability of the Ab fusion proteins to deliver proteins or DNA to cells growing in vitro; 3. Determine the properties of the Ab fusion proteins in vivo and their ability to target and eliminate tumors in animal models. I anticipate that the vector systems will provide powerful tools for treating a wide variety of important malignancies. The universal vectors will make it easier to treat tumors with multiple anti-cancer agents and will facilitate the rapid evaluation of potential new therapeutic agents. Although initial principles will be established using IL-2R and/or TfR as targets, future universal vectors can target other tumor associated molecules. Having been trained as an M.D./Ph.D., I have a strong grounding in both basic and clinical science. The training that I will receive during the time of this grant will enhance both my research skills and my facility with English. This additional training is necessary if I am to assume an independent position doing research at a major university. UCLA provides an excellent, supportive environment for the proposed research. There is a large faculty with expertise in virtually every discipline. Excellent seminar series and technical training sessions are available. The University is committed to my career development and will provide resources without requiring any teaching or clinical activities. The training period will also allow me to attend national and international meetings, both expanding my expertise and my network of collaborators and colleagues.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Subcommittee G - Education (NCI)
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Ojeifo, John O
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Daniels-Wells, Tracy R; Penichet, Manuel L (2016) Transferrin receptor 1: a target for antibody-mediated cancer therapy. Immunotherapy 8:991-4
Ortiz-Sánchez, E; Daniels, T R; Helguera, G et al. (2009) Enhanced cytotoxicity of an anti-transferrin receptor IgG3-avidin fusion protein in combination with gambogic acid against human malignant hematopoietic cells: functional relevance of iron, the receptor, and reactive oxygen species. Leukemia 23:59-70
Ortiz-Sanchez, Elizabeth; Helguera, Gustavo; Daniels, Tracy R et al. (2008) Antibody-cytokine fusion proteins: applications in cancer therapy. Expert Opin Biol Ther 8:609-32
Li, Gang; Andreansky, Samita; Helguera, Gustavo et al. (2008) A chaperone protein-enriched tumor cell lysate vaccine generates protective humoral immunity in a mouse breast cancer model. Mol Cancer Ther 7:721-9
Shi, Yijiang; Reiman, Tony; Li, Weiqun et al. (2007) Targeting aurora kinases as therapy in multiple myeloma. Blood 109:3915-21
Daniels, Tracy R; Ng, Patrick P; Delgado, Tracie et al. (2007) Conjugation of an anti transferrin receptor IgG3-avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells. Mol Cancer Ther 6:2995-3008
Helguera, Gustavo; Rodriguez, Jose A; Daniels, Tracy R et al. (2007) Long-term immunity elicited by antibody-cytokine fusion proteins protects against sequential challenge with murine mammary and colon malignancies. Cancer Immunol Immunother 56:1507-12
Rodriguez, Jose A; Helguera, Gustavo; Daniels, Tracy R et al. (2007) Binding specificity and internalization properties of an antibody-avidin fusion protein targeting the human transferrin receptor. J Control Release 124:35-42
Helguera, Gustavo; Rodriguez, Jose A; Penichet, Manuel L (2006) Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors. Mol Cancer Ther 5:1029-40
Daniels, Tracy R; Delgado, Tracie; Helguera, Gustavo et al. (2006) The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells. Clin Immunol 121:159-76

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