Cargando…

Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma

BACKGROUND: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell–mediated cytotoxicity of multiple myeloma cells in preclinical studies. OBJECTIVE: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patient...

Descripción completa

Detalles Bibliográficos
Autores principales: Girgis, Suzette, Lin, Shun Xin Wang, Pillarisetti, Kodandaram, Banerjee, Arnob, Stephenson, Tara, Ma, Xuewen, Shetty, Shoba, Yang, Tong-Yuan, Hilder, Brandi W., Jiao, Qun, Hanna, Brett, Adams, Homer C, Sun, Yu-Nien, Sharma, Amarnath, Smit, Jennifer, Infante, Jeffrey R., Goldberg, Jenna D., Elsayed, Yusri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345835/
https://www.ncbi.nlm.nih.gov/pubmed/35749004
http://dx.doi.org/10.1007/s11523-022-00893-y
_version_ 1784761519509078016
author Girgis, Suzette
Lin, Shun Xin Wang
Pillarisetti, Kodandaram
Banerjee, Arnob
Stephenson, Tara
Ma, Xuewen
Shetty, Shoba
Yang, Tong-Yuan
Hilder, Brandi W.
Jiao, Qun
Hanna, Brett
Adams, Homer C
Sun, Yu-Nien
Sharma, Amarnath
Smit, Jennifer
Infante, Jeffrey R.
Goldberg, Jenna D.
Elsayed, Yusri
author_facet Girgis, Suzette
Lin, Shun Xin Wang
Pillarisetti, Kodandaram
Banerjee, Arnob
Stephenson, Tara
Ma, Xuewen
Shetty, Shoba
Yang, Tong-Yuan
Hilder, Brandi W.
Jiao, Qun
Hanna, Brett
Adams, Homer C
Sun, Yu-Nien
Sharma, Amarnath
Smit, Jennifer
Infante, Jeffrey R.
Goldberg, Jenna D.
Elsayed, Yusri
author_sort Girgis, Suzette
collection PubMed
description BACKGROUND: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell–mediated cytotoxicity of multiple myeloma cells in preclinical studies. OBJECTIVE: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS: To estimate the efficacious therapeutic dosing range of teclistamab, pharmacokinetic (PK) data following the first cycle doses in the low-dose cohorts in the Phase I study were modeled using a 2-compartment model and simulated to predict the doses that would have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC(50) and EC(90) values from an ex vivo cytotoxicity assay). RESULTS: The doses predicted to have average serum concentrations between the EC(50) and EC(90) range were validated. In addition, simulations showed that weekly intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively, resulted in mean trough levels comparable to the maximum EC(90). The most active doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg subcutaneous doses selected as the recommended Phase II dose (RP2D). With active doses, exposure was maintained above the mean EC(90). All patients who responded to the RP2D of teclistamab had exposure above the maximum EC(90) in both serum and bone marrow on cycle 3, Day 1 of treatment. CONCLUSIONS: Our findings show that PK simulations of early clinical data together with ex vivo cytotoxicity estimates can inform the identification of a bispecific antibody’s therapeutic range. CLINICAL TRIAL REGISTRATION: NCT03145181, date of registration: May 9, 2017.
format Online
Article
Text
id pubmed-9345835
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Springer International Publishing
record_format MEDLINE/PubMed
spelling pubmed-93458352022-08-04 Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma Girgis, Suzette Lin, Shun Xin Wang Pillarisetti, Kodandaram Banerjee, Arnob Stephenson, Tara Ma, Xuewen Shetty, Shoba Yang, Tong-Yuan Hilder, Brandi W. Jiao, Qun Hanna, Brett Adams, Homer C Sun, Yu-Nien Sharma, Amarnath Smit, Jennifer Infante, Jeffrey R. Goldberg, Jenna D. Elsayed, Yusri Target Oncol Original Research Article BACKGROUND: Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell–mediated cytotoxicity of multiple myeloma cells in preclinical studies. OBJECTIVE: A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS: To estimate the efficacious therapeutic dosing range of teclistamab, pharmacokinetic (PK) data following the first cycle doses in the low-dose cohorts in the Phase I study were modeled using a 2-compartment model and simulated to predict the doses that would have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC(50) and EC(90) values from an ex vivo cytotoxicity assay). RESULTS: The doses predicted to have average serum concentrations between the EC(50) and EC(90) range were validated. In addition, simulations showed that weekly intravenous and subcutaneous doses of 0.70 mg/kg and 0.72 mg/kg, respectively, resulted in mean trough levels comparable to the maximum EC(90). The most active doses in the Phase I study were weekly intravenous doses of 0.27 and 0.72 mg/kg and weekly subcutaneous doses of 0.72 and 1.5 mg/kg, with the weekly 1.5 mg/kg subcutaneous doses selected as the recommended Phase II dose (RP2D). With active doses, exposure was maintained above the mean EC(90). All patients who responded to the RP2D of teclistamab had exposure above the maximum EC(90) in both serum and bone marrow on cycle 3, Day 1 of treatment. CONCLUSIONS: Our findings show that PK simulations of early clinical data together with ex vivo cytotoxicity estimates can inform the identification of a bispecific antibody’s therapeutic range. CLINICAL TRIAL REGISTRATION: NCT03145181, date of registration: May 9, 2017. Springer International Publishing 2022-06-24 2022 /pmc/articles/PMC9345835/ /pubmed/35749004 http://dx.doi.org/10.1007/s11523-022-00893-y Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
Girgis, Suzette
Lin, Shun Xin Wang
Pillarisetti, Kodandaram
Banerjee, Arnob
Stephenson, Tara
Ma, Xuewen
Shetty, Shoba
Yang, Tong-Yuan
Hilder, Brandi W.
Jiao, Qun
Hanna, Brett
Adams, Homer C
Sun, Yu-Nien
Sharma, Amarnath
Smit, Jennifer
Infante, Jeffrey R.
Goldberg, Jenna D.
Elsayed, Yusri
Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma
title Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma
title_full Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma
title_fullStr Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma
title_full_unstemmed Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma
title_short Translational Modeling Predicts Efficacious Therapeutic Dosing Range of Teclistamab for Multiple Myeloma
title_sort translational modeling predicts efficacious therapeutic dosing range of teclistamab for multiple myeloma
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345835/
https://www.ncbi.nlm.nih.gov/pubmed/35749004
http://dx.doi.org/10.1007/s11523-022-00893-y
work_keys_str_mv AT girgissuzette translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT linshunxinwang translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT pillarisettikodandaram translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT banerjeearnob translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT stephensontara translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT maxuewen translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT shettyshoba translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT yangtongyuan translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT hilderbrandiw translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT jiaoqun translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT hannabrett translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT adamshomerc translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT sunyunien translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT sharmaamarnath translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT smitjennifer translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT infantejeffreyr translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT goldbergjennad translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma
AT elsayedyusri translationalmodelingpredictsefficacioustherapeuticdosingrangeofteclistamabformultiplemyeloma