AGS62P1, a Novel Anti-FLT3 Antibody Drug Conjugate, Employing Site Specific Conjugation, Demonstrates Preclinical Anti-Tumor Efficacy in AML Tumor and Patient Derived Xenografts
| Autor: | Monica Leavitt, Pia M. Challita-Eid, Christopher Kemball, Liqing Jin, John E. Dick, Chunying Zhang, Gao Liu, Daniel S. Pereira, Michael Mattie, Zili An, Baljinder Randhawa, Hector Aviña, David R. Stover, Joseph D. Abad, Misty Vest, Faisal Malik, Josh Snyder, Brian A. Mendelsohn, Sher Karki, Christine Lowe, Banmeet Anand, Kendall Morrison, Ingrid B.J.K. Joseph, Peng Yang, Cyrus Virata, Nandini Rudra-Ganguly, Deanna L. Russell, Jeanette Grant, René Hubert, Fernando Donate |
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| Rok vydání: | 2015 |
| Předmět: |
Antibody-drug conjugate
biology medicine.diagnostic_test medicine.drug_class business.industry Immunology Cell hemic and immune systems Cell Biology Hematology Pharmacology Monoclonal antibody Biochemistry Receptor tyrosine kinase Flow cytometry fluids and secretions medicine.anatomical_structure In vivo hemic and lymphatic diseases embryonic structures medicine biology.protein Cytotoxic T cell business Tyrosine kinase |
| Zdroj: | Blood. 126:3806-3806 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v126.23.3806.3806 |
| Popis: | FLT3 (FMS-like tyrosine kinase 3) is a member of the class III receptor tyrosine kinase family, which is highly expressed in the blasts of both AML and ALL patients. In addition to FL ligand stimulation, FLT3 can also be activated by two distinct clusters of mutations: internal tandem duplications (FLT3/ITDs) in 20% to 25% patients and point mutations at position D835 in the tyrosine-kinase domain (FLT3/TKD) in 7% to 10% patients. FLT3 tyrosine kinase inhibitors (TKI) are mainly active against FLT3 mutant AML. An antibody drug conjugate (ADC), directed against the extracellular domain of FLT3 may only require FLT3 cell surface expression independent of mutation status. The restricted cellular distribution of FLT3 receptor and a higher expression in AML than in normal bone marrow makes FLT3 a favorable ADC target. Therefore, this ADC based strategy may offer a therapeutic alternative for AML patients independent of FLT3 status. Here, we report the preclinical assessment of a novel FLT3 targeting ADC, AGS62P1. AGS62P1 consists of a human anti-FLT3 monoclonal antibody, site specifically conjugated to a potent cytotoxic payload. FLT3 expression is confirmed in a large panel of AML and ALL tumor cells as well as in AML patient specimens via flow cytometry. The anti-leukemic activity of AGS62P1 was evaluated against AML and ALL tumor cell lines, in vitro and in vivo. AGS62P1 demonstrated strong binding affinity (0.1-0.5 nM) and potent cytotoxic activity in FLT3/ITD and Non-ITD tumor models, in vitro. Cytotoxic IC50 potency for AGS62P1 was 0.5-13 nM in FLT3/ITD and 0.2-12 nM in FLT3 non-ITD models. A fluorescence based assay confirmed that AGS62P1 is rapidly internalized in AML tumor cell lines. AGS62P1 is highly efficacious in FLT3/ITD and non-ITD tumor xenografts, leading to significant tumor growth inhibition or complete tumor regression. In primary AML patient xenograft drug treatment studies, the engraftment and outgrowth of 5/6 samples were significantly reduced when treated with AGS62P1. Taken together our data demonstrate that AGS62P1 exhibits potent antitumor activity against a broad panel of AML tumor models and primary AML samples, regardless of FLT3 status. We believe AGS62P1 may be an effective and alternative therapeutic for AML patients, which can bypass the TKI mediated resistance and deliver target specific effect through a different mode of action. Disclosures Jin: Agensys: Research Funding. Anand:Agensys: Employment. Dick:Agensys: Research Funding. |
| Databáze: | OpenAIRE |
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