The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies

Müller, Patrick; Milton, Mark; Lloyd, Peter; Sims, Jennifer; Brennan, Frank R.

doi:10.1016/j.copbio.2009.10.013

Cited by 124 publications

(73 citation statements)

References 19 publications

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“…In addition, the dose had been determined using the "no observed adverse effect level" (NOAEL) method that calculates dose based on risk, and where no adverse effect is observed in preclinical studies this dose can be overestimated. Since the TGN1412 trial, the "minimally anticipated biological effect level" (MABEL) has been recommended as a more appropriate basis for determining dose and allows dose-escalation studies to be based on minimal activation (27). In the aftermath of the trial, cytotoxicity was investigated by different researchers using different assay setups and found that the cytokine storm could actually have been predicted using human peripheral blood mononuclear cells with adapted …”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial

Chowdhury

Johnson

Glennie

et al. 2014

Cancer Immunology Research

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Immunostimulatory antibodies entering the clinic create challenge in terms of not only pharmacodynamics for monitoring anticipated mechanisms but also predetermining cytotoxicity. We show the use of ex vivo wholeblood samples to predict the activation requirements, cytokine signature, and adverse events of an anti-human-CD40 chimeric IgG1 antibody, ChiLob 7/4. Assessments were initially undertaken on human myeloid (mDC1) and plasmacytoid (pDC) dendritic cells, in which an absolute need for cross-linking was shown through the upregulation of activation markers CD83 and CCR7. Subsequent cytokine secretion evaluations of ex vivo whole blood showed the cross-linked antibody-induced increases in MIP1b, interleukin (IL)-8, IL-12, TNFa, and IL-6. This cytokine signature compared favorably with the Toll-like receptor (TLR) ligand lipopolysaccharide (LPS), in which levels of TNFa and IL-6 were significantly higher, suggesting a less intense proinflammatory response and possible modified cytokine release syndrome when used in human trials. Following first-in-human use of this agent within a dose escalation study, in vivo evaluations of dendritic cell activation and secreted cytokines closely matched the predetermined immunomonitoring endpoints. Patients showed a comparable pattern of MIP1b, IL-8, and IL-12 secretion, but no TNFa and IL-6 were identified. Mild symptoms relating to a cytokine release syndrome were seen at an equivalent dosage to that observed for dendritic cell activation and cytokine release. In summary, ChiLob 7/4 induces a distinctive pattern of dendritic cell activation and cytokine secretion in ex vivo assays that can be predictive of in vivo responses. Such preclinical approaches to monoclonal antibody evaluation may inform both the starting dosages and the anticipated cytokine release events that could occur, providing a valuable adjunct for future first-in-human assessments of immunostimulatory antibodies. Cancer Immunol Res; 2(3); 229-40. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial

Chowdhury

Johnson

Glennie

et al. 2014

Cancer Immunology Research

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“…Many reports have been published on the topic of FIH starting human dose selection for mAbs especially concerning MABEL for high-risk mAbs (54)(55)(56). Our approach to MABEL calculation is to apply a model-based approach to the selection of the starting dose, integrating as much mechanistic information as possible from all phases of preclinical discovery and development.…”

Section: Model-based Selection Of a Safe But Reasonable Starting Dosementioning

confidence: 99%

Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies

Luu

Kraynov

Kuang

et al. 2013

AAPS J

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Abstract. The industry-wide biopharmaceutical (i.e., biologic, biotherapeutic) pipeline has been growing at an astonishing rate over the last decade with the proportion of approved new biological entities to new chemical entities on the rise. As biopharmaceuticals appear to be growing in complexity in terms of their structure and mechanism of action, so are interpretation, analysis, and prediction of their quantitative pharmacology. We present here a modeling and simulation (M&S) framework for the successful preclinical development of monoclonal antibodies (as an illustrative example of biopharmaceuticals) and discuss M&S strategies for its implementation. Critical activities during early discovery, lead optimization, and the selection of starting doses for the first-in-human study are discussed in the context of pharmacokinetic-pharmacodynamic (PKPD) and M&S. It was shown that these stages of preclinical development are and should be reliant on M&S activities including systems biology (SB), systems pharmacology (SP), and translational pharmacology (TP). SB, SP, and TP provide an integrated and rationalized framework for decision making during the preclinical development phase. In addition, they provide increased target and systems understanding, describe and interpret data generated in vitro and in vivo, predict human PKPD, and provide a rationalized approach to designing the first-in-human study.

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“…More recently, the use of pharmacokinetic (PK) and pharmacodynamic (PD) modeling to derive biologically optimal dose levels from data from preclinical toxicology studies and in vivo pharmacology studies has increased [8]. The ideal process to determine the starting dose for BDPs is not defined [9] and is usually a balance between the highest safe dose of a drug and the lowest potentially active dose.…”

Section: Introductionmentioning

confidence: 99%

Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials

et al. 2015

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Background. First-in-human (FIH) trials of low-molecular-weight anticanceragents conventionallyderive a safe start dose (SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs). Materials and Methods. A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial. Results. The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the

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The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies

Cited by 124 publications

References 19 publications

Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial

Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial

Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies

Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials

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