Academic Journal
Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1(+) Activated T Cells ; Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells
| العنوان: | Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1(+) Activated T Cells ; Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells |
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| المؤلفون: | Dovedi, Simon J., Elder, Matthew J., Yang, Chunning, Sitnikova, Suzanne, I, Irving, Lorraine, Hansen, Anna, Hair, James, Jones, Des C., Hasani, Sumati, Wang, Bo, Im, Seock-Ah, Ben Tran, Subramaniam, Deepa S., Gainer, Shelby D., Vashisht, Kapil, Lewis, Arthur, Jin, Xiaofang, Kentner, Stacy, Mulgrew, Kathy, Wang, Yaya, Overstreet, Michael G., Dodgson, James, Wu, Yanli, Palazon, Asis, Morrow, Michelle, Rainey, Godfrey J., Browne, Gareth J., Neal, Frances, Murray, Thomas, V, Toloczko, Aleksandra D., Dall'Acqua, William, Achour, Ikbel, Freeman, Daniel J., Wilkinson, Robert W., Mazor, Yariv |
| المساهمون: | 임석아, Im, Seock-Ah |
| بيانات النشر: | American Association for Cancer Research Inc. |
| سنة النشر: | 2021 |
| المجموعة: | Seoul National University: S-Space |
| مصطلحات موضوعية: | ARM BINDING-EFFICIENCY, ANTIGEN-EXPRESSION, MOLECULAR-BASIS, TUMOR, TARGET, COMBINATION, MONOTHERAPY, ENGAGEMENT, EFFECTOR, AFFINITY |
| الوصف: | The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1(+) activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1(+) T cells versus PD-1(-) T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1(+) T cells. SIGNIFICANCE: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1(+) T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy. ; Y ; 1 |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 2159-8274 |
| Relation: | Cancer Discovery, Vol.11 No.5, pp.1100-1117; 134851; https://hdl.handle.net/10371/177231; 000648516100026; 2-s2.0-85106050234 |
| DOI: | 10.1158/2159-8290.CD-20-1445 |
| الاتاحة: | https://hdl.handle.net/10371/177231 https://doi.org/10.1158/2159-8290.CD-20-1445 |
| رقم الانضمام: | edsbas.39D0DB67 |
| قاعدة البيانات: | BASE |
| تدمد: | 21598274 |
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| DOI: | 10.1158/2159-8290.CD-20-1445 |