MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors

Brischwein, Klaus; Schlereth, Bernd; Guller, Benjamin; Steiger, Carola; Wolf, Andreas; Lutterbuese, Ralf; Offner, Sonja; Locher, Mathias; Urbig, Thomas; Raum, Tobias; Kleindienst, Petra; Wimberger, Pauline; Kimmig, Rainer; Fichtner, Iduna; Kufer, Peter; Hofmeister, Robert; Silva, Antonio J. da; Baeuerle, Patrick A.

doi:10.1016/j.molimm.2005.07.034

Cited by 235 publications

(207 citation statements)

References 56 publications

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“…Only patients treated at or above 24 µg/day achieved a solitomab C ss of at least 1 ng/mL required for efficient tumor cell lysis in vitro, 22 which likely contributed to the limited antitumor activity. The observed lymphocyte redistribution (and transient expression of T cell activation markers) was similar to what has been reported for the BiTE® antibody construct blinatumomab.…”

Section: Discussionmentioning

confidence: 99%

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Kebenko

Goebeler

Wolf³

et al. 2018

OncoImmunology

132

106

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We assessed the tolerability and antitumor activity of solitomab, a bispecific T-cell engager (BiTE®) antibody construct targeting epithelial cell adhesion molecule (EpCAM). Patients with relapsed/refractory solid tumors not amenable to standard therapy received solitomab as continuous IV infusion in a phase 1 dose-escalation study with six different dosing schedules. The primary endpoint was frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Sixty-five patients received solitomab at doses between 1 and 96 µg/day for ≥28 days. Fifteen patients had dose-limiting toxicities (DLTs): eight had transient abnormal liver parameters shortly after infusion start or dose escalation (grade 3, n = 4; grade 4, n = 4), and one had supraventricular tachycardia (grade 3); all events resolved with solitomab discontinuation. Six patients had a DLT of diarrhea: four events resolved (grade 3, n = 3; grade 4, n = 1), one (grade 3) was ongoing at the time of treatment-unrelated death, and one (grade 3) progressed to grade 5 after solitomab discontinuation. The maximum tolerated dose was 24 µg/day. Overall, 95% of patients had grade ≥3 treatment-related AEs, primarily diarrhea, elevated liver parameters, and elevated lipase. Solitomab half-life was 4.5 hours; serum levels plateaued within 24 hours. One unconfirmed partial response was observed. In this study of a BiTE® antibody construct targeting solid tumors, treatment of relapsed/refractory EpCAM-positive solid tumors with solitomab was associated with DLTs, including severe diarrhea and increased liver enzymes, which precluded dose escalation to potentially therapeutic levels.

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Section: Discussionmentioning

confidence: 99%

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Kebenko

Goebeler

Wolf³

et al. 2018

OncoImmunology

132

106

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“…For solid tumor indications such as these, eradication of cancer cells requires T‐cell infiltration and BiTE® antibody construct distribution into the tumors, with potentially more difficult pharmacodynamic assessments. AMG 110/MT 110, among the first BiTE® molecules developed, targets EpCAM (epithelial cell adhesion molecule), a protein widely expressed on adenocarcinoma 42. Mice were inoculated subcutaneously with various tumor cell lines and then injected intravenously with 89 Zr‐AMG 110 and imaged with positron emission tomography (PET).…”

Section: Mechanism Of Action and Key Characteristics Of Bite® Antibodmentioning

confidence: 99%

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

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Bispecific T‐cell Engagers (BiTE®) antibody constructs enable a polyclonal T‐cell response to cell‐surface tumor‐associated antigens, bypassing the narrow specificities of T‐cell receptors and the need for antigen presentation through the major histocompatibility complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs. Quantitative systems pharmacology is envisioned as a means to optimize dosing decisions for trials in which BiTE® antibody constructs are administered as monotherapy or in combination with other immunotherapies.

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“…and CD8 ? T cells by FACS [24]. Granzyme B levels were determined using the Cytofix/Cytoperm Fixation and Permeabilization Kit according to the manufacture's protocol (BD Biosciences Pharmingen, Heidelberg).…”

Section: Facs Analysis and Cytotoxicity Assaymentioning

confidence: 99%

“…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]. An Ep-CAM/CD3-bispecific antibody with specificity for the murine orthologs of EpCAM and CD3 has shown a significant therapeutic window, indicating that T cellrecruiting antibodies of this class can well distinguish between EpCAM antigen expressed on normal tissue and tumor tissue [28].…”

Section: Introductionmentioning

confidence: 99%

“…Several EpCAM (CD326)/CD3-bispecific antibodies have been shown in various mouse models to eradicate established tumors, to redirect tumor-resident T cells for lysis of metastatic human ovarian cancer tissue [24,29] and to effectively treat lung metastasis [30][31][32][33]. In a phase I/II study, advanced ovarian cancer patients were treated with the trifunctional bispecific antibody catumaxomab (anti-EpCAM 9 anti-CD3) resulting in a significant reduction of ascites flow rate [34].…”

Section: Introductionmentioning

confidence: 99%

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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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MT110: A novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors

Cited by 235 publications

References 56 publications

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

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

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