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Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1

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A Correction to this article was published on 01 April 2023

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Abstract

TYRP1-TCB is a CD3 T-cell bispecific (CD3-TCB) antibody for the treatment of advanced melanoma. A tumor growth inhibition (TGI) model was developed using mouse xenograft data with TYRP1-TCB monotherapy or TYRP1-TCB plus anti-PD-L1 combination. The model was translated to humans to inform a refined clinical strategy. From xenograft mouse data, we estimated an EC50 of 0.345 mg/L for TYRP1-TCB, close to what was observed in vitro using the same tumor cell line. The model showed that, though increasing the dose of TYRP1-TCB in monotherapy delays the time to tumor regrowth and promotes higher tumor cell killing, it also induces a faster rate of tumor regrowth. Combination with anti-PD-L1 extended the time to tumor regrowth by 25% while also decreasing the tumor regrowth rate by 69% compared to the same dose of TYRP1-TCB alone. The model translation to humans predicts that if patients’ tumors were scanned every 6 weeks, only 46% of the monotherapy responders would be detected even at a TYRP1-TCB dose resulting in exposures above the EC90. However, combination of TYRP1-TCB and anti-PD-L1 in the clinic is predicted to more than double the overall response rate (ORR), duration of response (DoR) and progression-free survival (PFS) compared to TYRP1-TCB monotherapy. As a result, it is highly recommended to consider development of CD3-TCBs as part of a combination therapy from the outset, without the need to escalate the CD3-TCB up to the Maximum Tolerated Dose (MTD) in monotherapy and without gating the combination only on RECIST-derived efficacy metrics.

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Funding

The present work was funded by F. Hoffmann—La Roche Ltd.

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Authors and Affiliations

  1. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland

    Javier Sánchez, Antje-Christine Walz, Candice Jamois, Stephen Fowler, Silke Simon & Nicolas Frances

  2. Department of Pharmacy, Uppsala University, Uppsala, Sweden

    Javier Sánchez & Lena E. Friberg

  3. Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland

    Valeria Nicolini, Linda Fahrni, Inja Waldhauer, Christian Klein & Pablo Umaña

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  1. Javier Sánchez
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Contributions

JS: conceptualization, formal analysis, methodology, validation, visualization, writing—original draft, writing—review and editing. VN: conceptualization, data curation, investigation, resources, supervision, writing—review and editing. LF: investigation, data curation, methodology, resources. IW: investigation, data curation, methodology, resources. AW: conceptualization, writing—review and editing. CJ: conceptualization, writing—review and editing. SF: conceptualization, writing—review and editing. SS: conceptualization, writing—review and editing. CK: supervision, writing—review and editing. PU: supervision, writing—review and editing. LF: conceptualization, writing—review and editing. NF: conceptualization, formal analysis, supervision, validation, writing—original draft, writing—review and editing.

Corresponding author

Correspondence to Javier Sánchez.

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Conflict of Interest

Javier Sánchez, Valeria Nicolini, Linda Fahrni, Inja Waldhauer, Antje-Christine Walz, Candice Jamois, Stephen Fowler, Silke Simon, Christian Klein, Pablo Umaña, and Nicolas Frances were Roche employees at the time this work was performed. Pablo Umaña and Christian Klein declare patents and stock ownership with Roche. Lena E. Friberg reports personal fees from Roche outside the submitted work. Experimental study protocol was reviewed and approved by local government authorities (ZH225-17).

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The original article has been updated to correct the name of the eleventh author from Lena Friberg to Lena E. Friberg.

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Sánchez, J., Nicolini, V., Fahrni, L. et al. Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1. AAPS J 24, 106 (2022). https://doi.org/10.1208/s12248-022-00755-5

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