Ganglioside GD2-specific trifunctional surrogate antibody Surek demonstrates therapeutic activity in a mouse melanoma model

Journal of Translational Medicine

Horst Lindhofer²  Christine Zehetmeier¹  Ivonne Suckstorff¹  Susanne Wosch¹  Matthias Plöscher²  Juergen Hess²  Ralph Mocikat³  Nina Eissler³  Beatrix Schäfer¹  Peter Ruf⁴ 

[1] TRION Research GmbH, Martinsried, Germany;TRION Pharma GmbH, Munich, Germany;Helmholtz-Zentrum München, Institut für Molekulare Immunologie, Munich, Germany;Department of Antibody Development, TRION Research GmbH, Am Klopferspitz 19, 82152, Martinsried, Germany

关键词: Melanoma;    Ganglioside GD2;    Trifunctional bispecific asntibody;    Immunotherapy;   

Others  :  828998
DOI  :  10.1186/1479-5876-10-219

 received in 2012-09-07, accepted in 2012-11-01,  发布年份 2012

【 摘 要 】

Background

Trifunctional bispecific antibodies (trAb) are a special class of bispecific molecules recruiting and activating T cells and accessory immune cells simultaneously at the targeted tumor. The new trAb Ektomab that targets the melanoma-associated ganglioside antigen GD2 and the signaling molecule human CD3 (hCD3) on T cells demonstrated potent T-cell activation and tumor cell destruction in vitro. However, the relatively low affinity for the GD2 antigen raised the question of its therapeutic capability. To further evaluate its efficacy in vivo it was necessary to establish a mouse model.

Methods

We generated the surrogate trAb Surek, which possesses the identical anti-GD2 binding arm as Ektomab, but targets mouse CD3 (mCD3) instead of hCD3, and evaluated its chemical and functional quality as a therapeutic antibody homologue. The therapeutic and immunizing potential of Surek was investigated using B78-D14, a B16 melanoma transfected with GD2 and GD3 synthases and showing strong GD2 surface expression. The induction of tumor-associated and autoreactive antibodies was evaluated.

Results

Despite its low affinity of approximately 10⁷ M^-1 for GD2, Surek exerted efficient tumor cell destruction in vitro at an EC₅₀ of 70ng/ml [0.47nM]. Furthermore, Surek showed strong therapeutic efficacy in a dose-dependent manner and is superior to the parental GD2 mono-specific antibody, while the use of a control trAb with irrelevant target specificity had no effect. The therapeutic activity of Surek was strictly dependent on CD4⁺ and CD8⁺ T cells, and cured mice developed a long-term memory response against a second challenge even with GD2-negative B16 melanoma cells. Moreover, tumor protection was associated with humoral immune responses dominated by IgG2a and IgG3 tumor-reactive antibodies indicating a Th1-biased immune response. Autoreactive antibodies against the GD2 target antigen were not induced.

Conclusion

Our data suggest that Surek revealed strong tumor elimination and anti-tumor immunization capabilities. The results warrant further clinical development of the human therapeutic equivalent antibody Ektomab.

【 授权许可】

   
2012 Ruf et al.; licensee BioMed Central Ltd.

【 图 表 】

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