BiTEs: bispecific antibody constructs with unique anti-tumor activity

Wolf, Evelyn; Hofmeister, Robert; Kufer, Peter; Schlereth, Bernd; Baeuerle, Patrick A.

doi:10.1016/s1359-6446(05)03554-3

Cited by 225 publications

(166 citation statements)

References 47 publications

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“…To date, a great variety of target cells have been tested for lysis mediated by BiTEs, and no fully resistant tumor cell line expressing the target antigen has been identified (Wolf et al, 2005). MT103, a CD19-specific BiTE, showed a high ex vivo response against blood samples from B-cell lymphoma patients (Loffler et al, 2003), and was efficacious in a severe combined immunodeficiency (SCID) mouse model (Dreier et al, 2003a).…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.

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Section: Bispecific Antibodiesmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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“…Consequently, BiTE Ò antibody constructs act independently of T cell receptor specificity, co-stimulatory or co-inhibitory signals, and peptide antigen presentation, thus bypassing several well-characterized mechanisms by which tumor cells evade immune recognition and destruction. 37 Some of the major functional characteristics of BiTE Ò antibody constructs that have been reported include a strict dependence on the presence of target cells for activation of T cells, 38 the creation of a functional cytolytic synapse, 39 serial T cell mediated lysis of target cells, 40 and highly potent redirected lysis of target cells. 41 In addition, neither antibody internalization nor T cell anergy were observed upon long-term treatment of tumor-bearing mice with a BiTE Ò antibody construct, suggesting that BiTE Ò antibody constructs themselves do not induce T cell anergy in the tumor microenvironment and can sustain an active T cell response during prolonged periods of T cell activation.…”

Section: Introductionmentioning

confidence: 99%

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Oberst¹,

Fuhrmann²,

Mulgrew³

et al. 2014

mAbs

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A Hammond (2014) CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas, mAbs, 6:6, 1571-1584, DOI: 10.4161/19420862.2014 To link to this article: https://doi.org/10. 4161/19420862.2014 Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE Ò antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.

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“…One example is the class of single-chain bispecific antibodies, which is designed to recruit and simultaneously activate T cells against target cells expressing a particular surface antigen [20][21][22]. Hallmarks of single-chain bispecific antibodies are a high potency of redirected lysis in the femtomolar range [23,24], a strictly target cell-dependent activation of T cells [25], serial lysis by activated T cells [26] and involvement of proper cytolytic synapses [27].…”

Section: Introductionmentioning

confidence: 99%

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

Witthauer

Schlereth

Brischwein

et al. 2008

Breast Cancer Res Treat

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In the present study, the efficacy of a new drug, i.e. the bispecific single-chain antibody MT110 targeting the epithelial antigen EpCAM and the T-cell antigen CD3 was tested ex vivo in malignant pleural effusions (MPEs). EpCAM ? epithelial cells were found in 78% of the MPEs (n = 18). Ex vivo treatment of seven MPEs resulted in a dose-dependent specific lysis of 37 ± 27% (±SD) EpCAM ? cells with 10 ng/ml (P = 0.03) and 57 ± 29.5% EpCAM ? cells with 1,000 ng/ml MT110 (P = 0.016) after 72 h. As a prerequisite for redirected lysis, stimulation of he autologous CD4 ? and CD8 ? cells in MPE by 1,000 ng/ml MT110 resulted in 21 ± 17% CD4 ? /CD25 ? and 29.4 ± 22% CD8 ? /CD25 ? cells (P = 0.016, respectively) after 72 h. This was confirmed by a 22-fold release of TNF-a and 230-fold release of IFN-c (1,000 ng/ml, 48 h, P = 0.03, respectively). Thus, relapsed breast cancer patients resistant to standard treatment might benefit from targeted therapy using MT110.Keywords Malignant pleural effusion Á Breast cancer Á Bispecific antibody Á EpCAM Á CD3 Á MT110 Á Ex vivo therapy

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BiTEs: bispecific antibody constructs with unique anti-tumor activity

Cited by 225 publications

References 47 publications

Novel antibodies as anticancer agents

Novel antibodies as anticancer agents

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

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