Patrick A Baeuerle

..The potential of global T-cell engagement for human cancer therapy by T-cell-engaging antibodies has yet to be fully investigated...

..Here we compared all anti-EpCAM antibodies in an attempt to explain differences in clinical activity and safety...

..Future research on EpCAM may benefit from a unified nomenclature and more frequent exchange among those who have been working on this cancer target during the past 30 years and will do so in the future...

..Recent results from clinical studies with a CD19/CD3-bispecific BiTE antibody suggest that this therapeutic paradigm is finally showing promise for treatment of both bulky and minimal residual disease...

..BiTE molecules therefore qualify for a highly controlled polyclonal T-cell therapy of cancer...

..MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas...

..Our study shows that BiTEs also have a high antitumor activity in immunocompetent mice and that there is no obvious need for costimulation of T cells by secondary agents...

..Finally, we show that muS110 and MT110 recognize orthologous epitopes on mouse and human EpCAM proteins, suggesting that the target-related safety profile of muS110 in mice may be predictive for MT110 in humans...

..A clinical trial testing prolonged administration of bscCD19xCD3 (MT103) for improving efficacy is currently ongoing...

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..Glucocorticoids thus qualify as a potential co-medication for therapeutic BiTE molecules and other cytotoxic T cell therapies for treatment of cancer...

..Moreover, our data suggest to routinely compare in mouse models human IgG1 and murine IgG2a versions of antibodies to properly assess the contribution of ADCC to overall anti-tumor activity...

..Because humans have extremely low numbers of EpCAM(+) cells in blood, this toxicity of an EpCAM-specific BiTE may be specific for mice...

..Our study shows that MT110 can efficiently gear up the potential of CD8(+) and CD4(+) T cells for serial lysis, and mediate kill of cancer cells predominantly through poreforming and pro-apoptotic components of cytotoxic T cell granules...

..To our knowledge, this is the first study showing that a bispecific antibody can sustain multiple rounds of target cell lysis by T cells...

..Combination of rituximab with blinatumomab was found to greatly enhance the activity of rituximab, in particular at low effector-to-target cell ratios and at low antibody concentration...

..The extraordinary potency of the BiTE class and its representative MT103 may translate into improved anti-tumor activity, lower dosing and lower costs of production compared to other bispecific antibody formats...

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..MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development...

..Together, our results reveal a unique opportunity for targeting cytotoxic T cells toward CEA-expressing tumors without being competitively inhibited by sCEA and establish CEA/CD3-bscAb as a promising and potent therapeutic approach...

..In case of the MCSP antigen, this provides the basis for selection of a maximally potent BiTE antibody candidate for development of a novel melanoma therapy...

..Our data show that the class of single-chain bispecific antibodies has very high antitumor efficacy in vivo and can use previously unstimulated T cells at low effector-to-target ratios...

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..Based on these results, anti-human NKG2D mAb E4 provides an ideal candidate for development of a novel therapeutic agent antagonizing a key receptor of NK and cytotoxic T cells with implications in autoimmune diseases...

..Our data suggest that D93 inhibits angiogenesis and tumor growth by blockade of cryptic bioactive signals on proteolyzed collagens with importance for growth of tumors and new blood vessels...

..Fusions between autoantigens and an anti-CD3 single-chain antibody may be suitable to develop very specific therapeutic approaches for the selective depletion of autoreactive B cells in autoimmune diseases...

..We conclude that soluble EpEX in sera of cancer patients is unlikely to pose an issue for the efficacy or safety of MT110, and perhaps other antibodies binding to N-terminal epitopes of EpCAM...

..These properties make bscCD19xCD3 superior to previously investigated CD19 bispecific Ab-based therapies...

..EGFR-specific BiTE antibodies may have potential to treat CRC that does not respond to conventional antibodies...

..MT204 has potential as a novel immunosuppressive and anti-proliferative therapy with an apparently broader spectrum of activities than anti-CD25 antibodies...

..Competition of serum IgG for binding of therapeutic IgG1 to NK cell may be one important reason why high antibody doses are required in the clinic for treatment of cancer by an ADCC-based mechanism...

..Our data demonstrate that specific antigen targeting via CD16 on M-DC8(+) DC is a promising vaccination approach for the efficient induction of specific CD4(+) T cell responses ex vivo, and perhaps in vivo...

..Here, we review the current progress in development of blinatumomab for treatment of patients with CD19-expressing hematological malignancies...

..In conclusion, bscCD19xCD3 could redirect unstimulated cytotoxic T cells against CD19-positive cells in an unexpectedly potent, rapid and specific fashion...

..T cells engaged by MT110 may provide a potent therapeutic means to eradicate TICs and bulk tumor cells derived thereof...

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..On the basis of these preclinical results, AMG 212/BAY2010112 appears as a promising new BiTE antibody for the treatment of patients with PSMA-expressing PCa...

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..EpCAM has oncogenic potential and is activated by release of its intracellular domain, which can signal into the cell nucleus by engagement of elements of the wnt pathway...

..As MCSP is expressed on most human melanomas, immunotherapy with MCSP/CD3-bispecific antibodies merits clinical investigation...

..Studying the mechanism of action of newly developed single-chain bispecific antibodies could provide insight into the shortcomings of bispecific antibodies that have been studied previously...

..Based on its favorable properties, MT203 has been selected for development as a novel anti-inflammatory human monoclonal antibody with therapeutic potential in a multitude of human autoimmune and inflammatory diseases...

..Our data suggest that blockade of cryptic epitopes exposed on collagen IV during angiogenesis and tumor growth by a monoclonal antibody may provide a novel therapeutic modality for treatment of cancer and pathogenic neo-vascularization...

..The fully human nature and the improved ADCC of MT201 with human effector cells will make MT201 a promising candidate for the clinical development of a novel pan-carcinoma antibody that is superior to edrecolomab...

..Such fusion proteins may provide a platform for the development of highly selective therapeutic approaches...

..We infer that selective elimination of M-DC8(+) cells in inflammatory diseases has therapeutic potential...

..High response rates and durable remissions are observed in first clinical trials, indicating that T cells can be potently redirected for efficient and lasting elimination of malignant cells...

..The characteristics of MT204, displaying linear pharmacokinetics, half-life in the range expected for a human IgG, benign safety profile and signs of efficacy, warrant further development of this antibody for therapy...

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..Although anti-CD95 antibody CH-11 failed to induce apoptosis in lymphoma cells, we provide evidence that B-CLL cell depletion by bscCD3 x CD3 is mediated at least in part by apoptosis via the caspase pathway...