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BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth

The EGFR and TGFβ signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFβ could help improve patient outcomes across various cancer types. Here, we deve...

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Autores principales: Boreddy, Srinivas Reddy, Nair, Reshmi, Pandey, Prashant Kumar, Kuriakose, Anshu, Marigowda, Shivakumar Bhadravathi, Dey, Chaitali, Banerjee, Arindam, Kulkarni, Hanumant, Sagar, Milind, Krishn, Shiv Ram, Rao, Shruthi, AR, Madhukara, Tiwari, Vinita, Alke, Bhavna, MV, Prashantha Kumar, Shri, Meena, Dhamne, Chaitrali, Patel, Sonal, Sharma, Pinky, Periyasamy, Sankar, Bhatnagar, Jaya, Kuriakose, Moni Abraham, Reddy, Ram Bhupal, Suresh, Amritha, Sreenivas, Suma, Govindappa, Nagaraja, Moole, Praveen Reddy, Bughani, Usha, Tan, Seng-Lai, Nair, Pradip
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10236157/
https://www.ncbi.nlm.nih.gov/pubmed/37074042
http://dx.doi.org/10.1158/0008-5472.CAN-21-4425
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author Boreddy, Srinivas Reddy
Nair, Reshmi
Pandey, Prashant Kumar
Kuriakose, Anshu
Marigowda, Shivakumar Bhadravathi
Dey, Chaitali
Banerjee, Arindam
Kulkarni, Hanumant
Sagar, Milind
Krishn, Shiv Ram
Rao, Shruthi
AR, Madhukara
Tiwari, Vinita
Alke, Bhavna
MV, Prashantha Kumar
Shri, Meena
Dhamne, Chaitrali
Patel, Sonal
Sharma, Pinky
Periyasamy, Sankar
Bhatnagar, Jaya
Kuriakose, Moni Abraham
Reddy, Ram Bhupal
Suresh, Amritha
Sreenivas, Suma
Govindappa, Nagaraja
Moole, Praveen Reddy
Bughani, Usha
Tan, Seng-Lai
Nair, Pradip
author_facet Boreddy, Srinivas Reddy
Nair, Reshmi
Pandey, Prashant Kumar
Kuriakose, Anshu
Marigowda, Shivakumar Bhadravathi
Dey, Chaitali
Banerjee, Arindam
Kulkarni, Hanumant
Sagar, Milind
Krishn, Shiv Ram
Rao, Shruthi
AR, Madhukara
Tiwari, Vinita
Alke, Bhavna
MV, Prashantha Kumar
Shri, Meena
Dhamne, Chaitrali
Patel, Sonal
Sharma, Pinky
Periyasamy, Sankar
Bhatnagar, Jaya
Kuriakose, Moni Abraham
Reddy, Ram Bhupal
Suresh, Amritha
Sreenivas, Suma
Govindappa, Nagaraja
Moole, Praveen Reddy
Bughani, Usha
Tan, Seng-Lai
Nair, Pradip
author_sort Boreddy, Srinivas Reddy
collection PubMed
description The EGFR and TGFβ signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFβ could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFβRII. The TGFβ “trap” fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGFβ by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer–cell activation, while suppressing VEGF secretion. In addition, BCA101 inhibited differentiation of naïve CD4(+) T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFβ “trap.” TGFβ in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFβRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR–expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy. SIGNIFICANCE: The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFβ to induce immune activation and to suppress tumor growth.
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spelling pubmed-102361572023-06-03 BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth Boreddy, Srinivas Reddy Nair, Reshmi Pandey, Prashant Kumar Kuriakose, Anshu Marigowda, Shivakumar Bhadravathi Dey, Chaitali Banerjee, Arindam Kulkarni, Hanumant Sagar, Milind Krishn, Shiv Ram Rao, Shruthi AR, Madhukara Tiwari, Vinita Alke, Bhavna MV, Prashantha Kumar Shri, Meena Dhamne, Chaitrali Patel, Sonal Sharma, Pinky Periyasamy, Sankar Bhatnagar, Jaya Kuriakose, Moni Abraham Reddy, Ram Bhupal Suresh, Amritha Sreenivas, Suma Govindappa, Nagaraja Moole, Praveen Reddy Bughani, Usha Tan, Seng-Lai Nair, Pradip Cancer Res Therapeutic Development and Chemical Biology The EGFR and TGFβ signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFβ could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFβRII. The TGFβ “trap” fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGFβ by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer–cell activation, while suppressing VEGF secretion. In addition, BCA101 inhibited differentiation of naïve CD4(+) T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFβ “trap.” TGFβ in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFβRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR–expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy. SIGNIFICANCE: The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFβ to induce immune activation and to suppress tumor growth. American Association for Cancer Research 2023-06-02 2023-04-19 /pmc/articles/PMC10236157/ /pubmed/37074042 http://dx.doi.org/10.1158/0008-5472.CAN-21-4425 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Therapeutic Development and Chemical Biology
Boreddy, Srinivas Reddy
Nair, Reshmi
Pandey, Prashant Kumar
Kuriakose, Anshu
Marigowda, Shivakumar Bhadravathi
Dey, Chaitali
Banerjee, Arindam
Kulkarni, Hanumant
Sagar, Milind
Krishn, Shiv Ram
Rao, Shruthi
AR, Madhukara
Tiwari, Vinita
Alke, Bhavna
MV, Prashantha Kumar
Shri, Meena
Dhamne, Chaitrali
Patel, Sonal
Sharma, Pinky
Periyasamy, Sankar
Bhatnagar, Jaya
Kuriakose, Moni Abraham
Reddy, Ram Bhupal
Suresh, Amritha
Sreenivas, Suma
Govindappa, Nagaraja
Moole, Praveen Reddy
Bughani, Usha
Tan, Seng-Lai
Nair, Pradip
BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth
title BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth
title_full BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth
title_fullStr BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth
title_full_unstemmed BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth
title_short BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth
title_sort bca101 is a tumor-targeted bifunctional fusion antibody that simultaneously inhibits egfr and tgfβ signaling to durably suppress tumor growth
topic Therapeutic Development and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10236157/
https://www.ncbi.nlm.nih.gov/pubmed/37074042
http://dx.doi.org/10.1158/0008-5472.CAN-21-4425
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