T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct

Schlereth, Bernd; Quadt, Cornelia; Dreier, Torsten; Kufer, Peter; Lorenczewski, Grit; Prang, Nadja; Brandl, Christian; Lippold, Sandra; Cobb, Kathy; Brasky, Kathleen M.; Leo, Eugen; Bargou, Ralf C.; Murthy, Krishna K.; Baeuerle, Patrick A.

doi:10.1007/s00262-005-0001-1

Cited by 87 publications

(49 citation statements)

References 25 publications

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“…A key difference was EpCAM expression on mouse lymphocytes, which was not seen on human lymphocytes. As reported for the B-lymphocyte-specific BiTE antibody MT103 in chimpanzee, the immediate encounter of T cells and B target cells in blood can cause transient cytokine release by MT103 (47). This may be less pronounced with a BiTE targeting localized EpCAM target in tumor tissue.…”

Section: Murine-specific Epcam Bitementioning

confidence: 96%

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

Amann¹,

Brischwein²,

Lutterbuese³

et al. 2008

Cancer Research

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EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibodybased immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 Mg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 Mg/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant therapeutic window for an EpCAM-specific BiTE antibody in mice. 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. [Cancer Res 2008;68(1):143-51]

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Section: Murine-specific Epcam Bitementioning

confidence: 96%

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

Amann¹,

Brischwein²,

Lutterbuese³

et al. 2008

Cancer Research

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“…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). It has been shown in chimpanzees that MT103 causes cumulative loss of peripheral B lymphocytes (Schlereth et al, 2006). A clinical trial testing the prolonged administration of bscCD19xCD3 (MT103) for improving efficacy is currently ongoing.…”

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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“…15 The CD19xCD3 BiTE molecule (blinatumomab) was further evaluated in chimpanzees, and significant B-cell depletion was observed. 16 Moreover, results from early clinical studies of blinatumomab have demonstrated impressive response rates in both relapsing nonHodgkin lymphoma and B-cell acute lymphoblastic leukemia patients, supporting further evaluation of this potential therapeutic avenue. 17 Despite this success, scFv-based bispecific strategies have limitations, including constraints imparted by the linker sequences that connect the V regions in a "nonnatural" manner, resulting in reduced or altered antigen recognition and potency.…”

Section: Introductionmentioning

confidence: 99%

Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma

Moore

Zhang

Rainey

et al. 2011

Blood

235

202

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IntroductionTargeted mAb-based therapies provide effective and safe treatments for hematologic malignancies. Rituximab, which specifically targets the B-cell antigen CD20, has had the greatest success, revolutionizing the treatment of the 2 most common forms of nonHodgkin lymphoma: follicular and diffuse large B-cell lymphoma. In addition, mAb-based therapies targeting CD52 (alemtuzumab) and CD33 (gemtuzumab ozogamicin) have been approved for the treatment of chronic lymphocytic leukemia and acute myelogenous leukemia, respectively. Despite the progress of these strategies, they do have limitations. Only a fraction of patients respond to rituximab, and the majority of those who do respond will eventually relapse. Treatment with alemtuzumab and gemtuzumab are limited by safety concerns, and many additional hematologic malignancies do not respond to treatment with any of these targeted therapies. Various therapies based on alternate mAbs, including second-generation anti-CD20 mAbs and those targeting alternate cell-surface proteins such as CD19, CD22, CD30, CD37, CD40, and CD74, have been developed and are at different stages of clinical testing in the hopes of providing approaches to treating a broader spectrum of hematologic malignancies that are poorly served by existing therapies. 1,2 Whereas targeting of cell-surface antigens themselves can mediate antitumor activity through the induction of apoptosis, most mAb-based activity against hematologic malignancies is reliant on either Fc-mediated effector functions such as complementdependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity 3,4 or is engineered through the conjugation of an immunotoxin or radiolabeled isotope. 1 Considering the potential of naturally occurring CTLs to mediate cell lysis, various strategies have also been explored to recruit CTLs to mediate tumor cell killing. Tumor-specific CTLs exert extremely potent effects through recognition of the corresponding peptide/MHC complex recognized by their TCR, and are among the most potent cells that mediate antitumor effects. A major limitation in generating tumorspecific CTLs in vivo is that their induction requires the use of vaccine strategies, such as dendritic cell-based vaccines, 5 that are capable of breaking tolerance to cancer self-antigens. One alternative is ex vivo expansion and activation of rare, tumor-specific CTLs for reinfusion into cancer patients. 6 However, cancer cells can down-regulate MHC expression as an escape mechanism, thus preventing the ability of CTLs to recognize their antigenic peptide. The genetic manipulation of patients' T cells to express chimeric antigen receptors comprising a tumor-specific antigen and T cellactivating properties before their adoptive transfer provides a non-MHC-restricted approach to targeting cancer, as was shown recently in the treatment of lymphoma with T cells engineered to recognize CD19. 7 However, the patient-specific manipulation and risk associated with this procedure represent major limitations to its expanded use. Alt...

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T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct

Cited by 87 publications

References 25 publications

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

Novel antibodies as anticancer agents

Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma

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