We have developed an antibody fusion protein composed of avidin fused to a human IgG3 specific for the transferrin receptor (TfR). Our initial goal was to use this molecule (anti-TfR IgG3-Av) as a universal vector to deliver biotinylated agents into cancer cells. We have found that anti-TfR IgG3-Av effectively delivers biotinylated molecules into cancer cells by receptor mediated endocytosis and that these molecules remain active after their internalization. Furthermore, we have unexpectedly discovered that anti-TfR IgG3-Av, but not a recombinant anti-TfR IgG3 or a non-specific IgG3-Av, possesses a strong intrinsic antiproliferative/pro-apoptotic activity against hematopoietic malignant cell lines. Importantly, this cytotoxic activity may be further enhanced by the addition of biotinylated compounds. We now hypothesize that anti-TfR IgG3-Av can be used alone or in combination with other agents as a novel drug against an incurable plasma cell malignancy: multiple myeloma (MM). We propose to determine the effect of anti-TfR IgG3-Av on both proliferation and apoptosis of selected human MM cell lines and to define the mechanism responsible for the inhibition of proliferation and induction of apoptosis. We will also examine the additive/synergistic effect ? of combining anti-TfR IgG3-Av with other cytotoxic/sensitizing agents, such as biotinylated Pseudomonas exotoxin A (PE) and drugs currently used in the treatment of MM such as Thalidomide and Dexamethasone. Based on our findings we will test the efficacy of anti-TfR IgG3-Av alone or combined with other anti-cancer drugs against primary myeloma cells obtained from MM patients and against human MM tumors growing in immunodeficient mice. Thus, the proposed experiments will result in a better understanding of the mechanism of action of anti-TfR IgG3-Av and will indicate if this novel therapeutic has potential for use in the treatment of MM. We anticipate that the utility of this therapeutic will not be restricted to the elimination of myeloma cells in vivo but can also be used for in vitro approaches including the efficient purging of myeloma cells during ex vivo expansion of hematopoietic progenitor-cells for use in autologous transplantation in MM patients. We would like to stress that the impact of the results obtained from the present studies is not restricted to MM. Similar approaches can be applied to other hematopoietic malignancies such as leukemias and lymphomas. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Developmental Therapeutics Study Section (DT)
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Yovandich, Jason L
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Leoh, Lai Sum; Kim, Yoon Kyung; Candelaria, Pierre V et al. (2018) Efficacy and Mechanism of Antitumor Activity of an Antibody Targeting Transferrin Receptor 1 in Mouse Models of Human Multiple Myeloma. J Immunol 200:3485-3494
Daniels-Wells, Tracy R; Penichet, Manuel L (2016) Transferrin receptor 1: a target for antibody-mediated cancer therapy. Immunotherapy 8:991-4
Kaufhold, Samantha; Garbán, Hermes; Bonavida, Benjamin (2016) Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res 35:84
Daniels-Wells, Tracy R; Widney, Daniel P; Leoh, Lai Sum et al. (2015) Efficacy of an Anti-transferrin Receptor 1 Antibody Against AIDS-related Non-Hodgkin Lymphoma: A Brief Communication. J Immunother 38:307-10
Leoh, Lai Sum; Daniels-Wells, Tracy R; Martínez-Maza, Otoniel et al. (2015) Insights into the effector functions of human IgG3 in the context of an antibody targeting transferrin receptor 1. Mol Immunol 67:407-15
Bonavida, Benjamin (2014) RKIP-mediated chemo-immunosensitization of resistant cancer cells via disruption of the NF-?B/Snail/YY1/RKIP resistance-driver loop. Crit Rev Oncog 19:431-45
Leoh, Lai Sum; Morizono, Kouki; Kershaw, Kathleen M et al. (2014) Gene delivery in malignant B cells using the combination of lentiviruses conjugated to anti-transferrin receptor antibodies and an immunoglobulin promoter. J Gene Med 16:11-27
VanderWall, Kristina; Daniels-Wells, Tracy R; Penichet, Manuel et al. (2013) Iron in multiple myeloma. Crit Rev Oncog 18:449-61
Widney, Daniel P; Olafsen, Tove; Wu, Anna M et al. (2013) Levels of murine, but not human, CXCL13 are greatly elevated in NOD-SCID mice bearing the AIDS-associated Burkitt lymphoma cell line, 2F7. PLoS One 8:e72414
Daniels-Wells, Tracy R; Helguera, Gustavo; Rodríguez, José A et al. (2013) Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1. Toxicol In Vitro 27:220-31

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