A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3

Mau-Sørensen, Morten; Dittrich, Christian; Dienstmann, Rodrigo; Lassen, Ulrik; Büchler, Wilfried; Martinius, Holger; Tabernero, Josep

doi:10.1007/s00280-015-2728-5

Cited by 52 publications

(42 citation statements)

References 24 publications

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“…However, catumaxomab appears to mediate a target-independent interaction between Fcγ and Kupffer cells in the liver. 21 The exact mechanism leading to changes in liver parameters after the start of solitomab infusion or after dose escalation remains unclear. A current hypothesis proposes that solitomab administration may lead to local lysis of EpCAM-positive cells in the liver, accompanied by transient and localized release of proinflammatory cytokines by involved cytotoxic T cells.…”

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

126

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

126

106

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“…For example, in clinical trials involving T-cellactivating therapies, patients need to be monitored for hemophagocytic lymphohistiocytosis and any other symptoms of cytokinerelated illnesses (28). Severe reactions have been reported with CD3-directed TDBs in the clinic (28), including death in EpCAM/ CD3 TDB phase I clinical trials (29), all of which resulted from overactivation of T cells. Although our model was beneficial in determining a more clinically relevant tissue distribution by actively binding the mouse's T cells, it is still not a valid safety model and these efforts will be reported elsewhere.…”

Section: Discussionmentioning

confidence: 99%

Relative Target Affinities of T-Cell–Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

Mandikian¹,

Takahashi

Lo³

et al. 2018

Molecular Cancer Therapeutics

109

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Anti-HER2/CD3, a T-cell-dependent bispecific antibody (TDB) construct, induces T-cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. Although therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen-binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy. To our knowledge, no distribution studies have been published using preclinical models wherein the T-cell-targeting arm of the TDB is actively bound to T cells. We used a combined approach involving radiochemistry, invasive biodistribution, and noninvasive single-photon emission tomographic (SPECT) imaging to measure TDB distribution and catabolism in transgenic mice with human CD3ε expression on T cells. Using CD3 affinity variants, we assessed the impact of CD3 affinity on short-term pharmacokinetics, tissue distribution, and cellular uptake. Our experimental approach determined the relative effects of (i) CD3 targeting to normal tissues, (ii) HER2 targeting to HER2-expressing tumors, and (iii) relative HER2/CD3 affinity, all as critical drivers for TDB distribution. We observed a strong correlation between CD3 affinity and distribution to T-cell-rich tissues, with higher CD3 affinity reducing systemic exposure and shifting TDB distribution away from tumor to T-cell-containing tissues. These observations have important implications for clinical translation of bispecific antibodies for cancer immunotherapy. .

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“…To mitigate toxicities, including CRS, and to achieve efficacious doses, an intrapatient “priming” dose strategy has been investigated for T‐BsAbs, where a lower initial dose is followed by higher maintenance doses. It is based on the observation that cytokine levels as well as CRS severity seem to attenuate upon repeated dosing . This “priming” effect enables a higher maintenance dose to ultimately be reached.…”

mentioning

confidence: 99%

A Modeling Framework to Characterize Cytokine Release upon T‐Cell–Engaging Bispecific Antibody Treatment: Methodology and Opportunities

Chen

Kamperschroer²,

Wong

et al. 2019

Clinical Translational Sci

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T‐cell–engaging bispecific antibodies (T‐BsAbs) are an important class of antibody therapeutics in immuno‐oncology. T‐BsAbs simultaneously bind to CD3 on T cells and a tumor‐associated antigen on tumor cells, activate T cells, and redirect T cells’ cytotoxicity against tumor cells. Cytokine release syndrome (CRS), a common dose‐limiting adverse event for T‐BsAbs, is associated with T‐cell activation. A “priming” dose strategy (i.e., a lower initial dose followed by a higher maintenance dose) has been implemented in the clinic to mitigate CRS and to achieve efficacious doses with T‐BsAbs. So far, the selection of the optimal priming dosing regimen is largely empirical. A “fit‐for‐purpose” semimechanistic pharmacokinetic/pharmacodynamic model was developed to characterize the cytokine release profiles upon T‐BsAb treatment, including the priming effect observed with repeated dosing. This model can be utilized to simulate cytokine profiles following various dosing regimens and may assist the design of clinical dosing strategies for T‐BsAbs programs.

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A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3

Abstract: The MTD of weekly intravenous catumaxomab was 7 µg. Major toxicities were cytokine release-related symptoms and hepatotoxicity.

Cited by 52 publications

References 24 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

Relative Target Affinities of T-Cell–Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

A Modeling Framework to Characterize Cytokine Release upon T‐Cell–Engaging Bispecific Antibody Treatment: Methodology and Opportunities

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