Abstract 4624: High affinity CD3 RECRUIT-TandAbs for T cell-mediated lysis of malignant CD19+ B cells
| Autor: | Stefan Knackmuss, Uwe Reusch, Eugene Zhukovsky, Melvyn Little, Ivica Fucek, Thomas Gronewold, Markus Eser, Fionnuala McAleese, Carmen Burkhardt |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Cancer Research. 72:4624-4624 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | The TandAb technology enables the development of innovative antibody therapeutics for improved treatment of various diseases. This platform has been primarily applied to oncology and comprises of CD3 RECRUIT- and CD16A RECRUIT-TandAbs for activation of T and NK effector cells, respectively, and lysis of target cells expressing specific surface antigens. The CD3 RECRUIT-TandAb AFM11 is a human bispecific tetravalent antibody with two binding sites for the α-chain of CD3 and two binding sites for CD19. CD19 is expressed at early stages of B cell development and persists until the final differentiation into plasma cells. Thus, CD19 represents an attractive target for the treatment of various B cell malignancies including leukemias and lymphomas that lack CD20 expression or are refractory to anti-CD20 antibody therapies. In vitro cytotoxicity assays employing tumor cell lines demonstrate high potency of AFM11 in mediating target cell lysis: EC50 values are in the low to sub-picomolar range depending on CD19+ target cell lines and primary B-CLL tumor cells. Cytotoxic activity of tetravalent AFM11 is superior to those of alternative bivalent antibody formats. High affinity binding of AFM11 to CD3 and CD19 (low to sub-nanomolar range) contributes to efficacious T cell recruitment. This binding was determined by flow cytometry and by a label-free biosensor that measures real-time binding kinetics on live cells. Therapeutic recruitment of T cells has a potential for a devastating cytokine release if it results not in a site-specific but rather systemic activation. Thus, functional in vitro assays were used to demonstrate that high affinity and bivalent binding of AFM11 to CD3 is not sufficient for triggering activation signals in T cells. AFM11 activates T cells only in the presence of CD19+ target cells, and specifically mediates lysis of these cells without affecting antigen-negative bystander cells. In the absence of target cells and at high concentrations AFM11 induces down-modulation of the CD3/TCR complex from the surface of T cells. The latter may contribute additional safety to therapeutic potential of CD3 RECRUIT-TandAbs without affecting the efficacy, since AFM11-treated T cells can be re-engaged for target cell lysis. In vivo AFM11 demonstrated a robust dose-dependent inhibition of tumor growth in a study with Raji xenografts in NOD/scid mice and reconstituted human PBMC. Altogether, these data suggest that AFM11 is a highly efficacious novel drug candidate for the treatment of hematological malignancies and displays an advantageous safety profile. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4624. doi:1538-7445.AM2012-4624 |
| Databáze: | OpenAIRE |
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