Abstract
Trifunctional bispecific antibodies (trAb) are novel anticancer drugs that recruit and activate different types of immune effector cells at the targeted tumor. Thus, tumor cells are effectively eliminated and a long-lasting tumor-specific T-cell memory is induced. The trAb Ektomab is directed against human CD3 on T cells and the tumor-associated ganglioside GD2, which is an attractive target for immunotherapy of melanoma in humans. To optimize clinical applicability, we studied different application routes with respect to therapeutic efficacy and tolerability by using the surrogate trAb Surek (anti-GD2 × anti-murine CD3) and a murine melanoma engineered to express GD2. We show that subcutaneous injection of the trAb is superior to the intravenous delivery pathway, which is the standard application route for therapeutic antibodies. Despite lower plasma levels after subcutaneous administration, the same tumor-protective potential was observed in vivo compared with intravenous administration of Surek. However, subcutaneously delivered Surek showed better tolerability. This could be explained by a continuous release of the antibody leading to constant plasma levels and a delayed induction of proinflammatory cytokines. Importantly, the induction of counter-regulatory mechanisms was reduced after subcutaneous application. These findings are relevant for the clinical application of trifunctional bispecific antibodies and, possibly, also other immunoglobulin constructs. Mol Cancer Ther; 14(8); 1877-83. ©2015 AACR.
Highlights
Treatment of cancer has substantially improved during the past years, the prognosis of many malignancies is still poor
Using the B16F0-derived murine melanoma cell line B78D14, which is engineered to express GD2 [13], and Trifunctional bispecific antibodies (trAb) Surek as a surrogate construct for Ektomab, we previously demonstrated that this approach is highly effective in terms of eliminating melanoma cells [6, 14, 15]
Therapeutic efficacy of subcutaneously delivered Surek As already shown, the in vivo efficacy of trAbs is reflected by T
Summary
Treatment of cancer has substantially improved during the past years, the prognosis of many malignancies is still poor. Trifunctional bispecific antibodies (trAb) are promising reagents that harness the immune system to reject cancer [1]. These novel therapeutic antibodies consist of two different binding arms, which are directed against a tumor-associated antigen and CD3 on T cells, respectively. They are endowed with an intact Fc region (comprising a rat and a mouse moiety) that. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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