A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(+) tumor cells.
In: MAbs, Jg. 7 (2015), Heft 3, S. 584-604
Online
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Zugriff:
To harness the potent tumor-killing capacity of T cells for the treatment of CD19(+) malignancies, we constructed AFM11, a humanized tetravalent bispecific CD19/CD3 tandem diabody (TandAb) consisting solely of Fv domains. The molecule exhibits good manufacturability and stability properties. AFM11 has 2 binding sites for CD3 and 2 for CD19, an antigen that is expressed from early B cell development through differentiation into plasma cells, and is an attractive alternative to CD20 as a target for the development of therapeutic antibodies to treat B cell malignancies. Comparison of the binding and cytotoxicity of AFM11 with those of a tandem scFv bispecific T cell engager (BiTE) molecule targeting the same antigens revealed that AFM11 elicited more potent in vitro B cell lysis. Though possessing high affinity to CD3, the TandAb mediates serial-killing of CD19(+) cells with little dependence of potency or efficacy upon effector:target ratio, unlike the BiTE. The advantage of the TandAb over the BiTE was most pronounced at lower effector:target ratios. AFM11 mediated strictly target-dependent T cell activation evidenced by CD25 and CD69 induction, proliferation, and cytokine release, notwithstanding bivalent CD3 engagement. In a NOD/scid xenograft model, AFM11 induced dose-dependent growth inhibition of Raji tumors in vivo, and radiolabeled TandAb exhibited excellent localization to tumor but not to normal tissue. After intravenous administration in mice, half-life ranged from 18.4 to 22.9 h. In a human ex vivo B-cell chronic lymphocytic leukemia study, AFM11 exhibited substantial cytotoxic activity in an autologous setting. Thus, AFM11 may represent a promising therapeutic for treatment of CD19(+) malignancies with an advantageous safety risk profile and anticipated dosing regimen.
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A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(+) tumor cells.
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Autor/in / Beteiligte Person: | Reusch, U ; Duell, J ; Ellwanger, K ; Herbrecht, C ; Knackmuss, SH ; Fucek, I ; Eser, M ; McAleese, F ; Molkenthin, V ; Gall, FL ; Topp, M ; Little, M ; Zhukovsky, EA |
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Zeitschrift: | MAbs, Jg. 7 (2015), Heft 3, S. 584-604 |
Veröffentlichung: | 2015- : Philadelphia, PA : Taylor & Francis ; <i>Original Publication</i>: Austin, TX : Landes Bioscience, 2015 |
Medientyp: | academicJournal |
ISSN: | 1942-0870 (electronic) |
DOI: | 10.1080/19420862.2015.1029216 |
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