First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ..
BACKGROUND: First-in-human (FIH) clinical trials require careful selection of a safe yet biologically relevant starting dose. Typically, such starting doses are selected based on toxicity studies in a pharmacologically relevant animal model. However, with the advent of target-specific and highly active immunotherapeutics, both the Food and Drug Administration and the European Medicines Agency have provided guidance that recommend determining a safe starting dose based on a minimum anticipated biological effect level (MABEL) approach.
METHODS: We recently developed a T cell activating bispecific antibody that effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma in mice (hEGFRvIII:CD3 bi-scFv). hEGFRvIII:CD3 bi-scFv is comprized of two single chain antibody fragments (bi-scFvs) that bind mutant epidermal growth factor receptor variant III (EGFRvIII), a mutation frequently seen in malignant glioma, and human CD3ε on T cells, respectively. In order to establish a FIH dose, we used a MABEL approach to select a safe starting dose for hEGFRvIII:CD3 bi-scFv, based on a combination of in vitro data, in vivo animal studies, and theoretical human receptor occupancy modeling.
RESULTS: Using the most conservative approach to the MABEL assessment, a dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/kg body weight was selected as a safe starting dose for a FIH clinical study.
CONCLUSIONS: The comparison of our MABEL-based starting dose to our in vivo efficacious dose and the theoretical human receptor occupancy strongly supports that our human starting dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/patient kg will be safe.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 8(2020), 1 vom: 22. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schaller, Teilo H [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.03.2021 Date Revised 05.05.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2019-000213 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308584902 |
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| 100 | 1 | |a Schaller, Teilo H |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach |
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| 500 | |a Date Revised 05.05.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. | ||
| 520 | |a BACKGROUND: First-in-human (FIH) clinical trials require careful selection of a safe yet biologically relevant starting dose. Typically, such starting doses are selected based on toxicity studies in a pharmacologically relevant animal model. However, with the advent of target-specific and highly active immunotherapeutics, both the Food and Drug Administration and the European Medicines Agency have provided guidance that recommend determining a safe starting dose based on a minimum anticipated biological effect level (MABEL) approach | ||
| 520 | |a METHODS: We recently developed a T cell activating bispecific antibody that effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma in mice (hEGFRvIII:CD3 bi-scFv). hEGFRvIII:CD3 bi-scFv is comprized of two single chain antibody fragments (bi-scFvs) that bind mutant epidermal growth factor receptor variant III (EGFRvIII), a mutation frequently seen in malignant glioma, and human CD3ε on T cells, respectively. In order to establish a FIH dose, we used a MABEL approach to select a safe starting dose for hEGFRvIII:CD3 bi-scFv, based on a combination of in vitro data, in vivo animal studies, and theoretical human receptor occupancy modeling | ||
| 520 | |a RESULTS: Using the most conservative approach to the MABEL assessment, a dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/kg body weight was selected as a safe starting dose for a FIH clinical study | ||
| 520 | |a CONCLUSIONS: The comparison of our MABEL-based starting dose to our in vivo efficacious dose and the theoretical human receptor occupancy strongly supports that our human starting dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/patient kg will be safe | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a immunology | |
| 650 | 4 | |a neurooncology | |
| 650 | 4 | |a oncology | |
| 650 | 4 | |a pharmacokinetics | |
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| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a CD3 Complex |2 NLM | |
| 650 | 7 | |a CD3E protein, human |2 NLM | |
| 650 | 7 | |a epidermal growth factor receptor VIII |2 NLM | |
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| 700 | 1 | |a Snyder, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Spasojevic, Ivan |e verfasserin |4 aut | |
| 700 | 1 | |a Gedeon, Patrick C |e verfasserin |4 aut | |
| 700 | 1 | |a Sanchez-Perez, Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Sampson, John H |e verfasserin |4 aut | |
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