Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
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DOI：
10.1016/j.ccell.2018.02.010
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发表时间：
2018-04-09
期刊：
影响因子：
50.3
通讯作者：
Quezada SA
中科院分区：
文献类型：
--
作者：
Arce Vargas F;Furness AJS;Litchfield K;Joshi K;Rosenthal R;Ghorani E;Solomon I;Lesko MH;Ruef N;Roddie C;Henry JY;Spain L;Ben Aissa A;Georgiou A;Wong YNS;Smith M;Strauss D;Hayes A;Nicol D;O'Brien T;Mårtensson L;Ljungars A;Teige I;Frendéus B;TRACERx Melanoma;TRACERx Renal;TRACERx Lung consortia;Pule M;Marafioti T;Gore M;Larkin J;Turajlic S;Swanton C;Peggs KS;Quezada SA
通过使用表达人类fc - γ受体（fc - γ rs）的小鼠模型，我们证明了ipilimumab和tremelimumab等同型抗体在体内介导肿瘤内调节性T （Treg）细胞消耗，增加CD8+与Treg细胞的比例，促进肿瘤排斥反应。具有改进的fc - γ - r结合谱的抗体具有更好的抗肿瘤反应和生存率。在晚期黑色素瘤患者中，对ipilimumab的反应与CD16a-V158F高亲和力多态性相关。这种活性只出现在炎症性肿瘤的情况下，解释了在临床环境中观察到的适度反应率。我们的数据表明，炎症肿瘤中的抗ctla -4活性可能通过增强fc - γ - r结合而得到改善，而浸润不良的肿瘤可能需要联合治疗。hIgG1和hIgG2同型的抗ctla -4促进肿瘤内Treg细胞的消耗hIgG2抗体通过CD32a介导肿瘤内Treg细胞的体内消耗具有增强Fc效应功能的抗ctla -4改善治疗结果CD16-V158F SNP与炎症肿瘤中易普利姆单抗的反应相关Arce Vargas等人使用表达人类Fcγ rs的小鼠模型表明，具有等同易普利姆单抗同型的抗体通过消耗CD8+与Treg的比率增加肿瘤内Tregs促进肿瘤排斥反应。在黑色素瘤患者中，对伊匹单抗的反应与高亲和力的FcγR多态性相关。
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches. Anti-CTLA-4 of hIgG1 and hIgG2 isotypes promote depletion of intra-tumoral Treg cells hIgG2 antibodies mediate in vivo depletion of intra-tumoral Treg cells via CD32a Anti-CTLA-4 with enhanced Fc effector function improves therapeutic outcomes The CD16-V158F SNP is associated with response to ipilimumab in inflamed tumors Arce Vargas et al. use a mouse model expressing human FcγRs to show that antibodies with isotypes equivalent to ipilimumab increase the CD8+ to Treg ratio by depleting intra-tumoral Tregs to promote tumor rejection. In melanoma patients, response to ipilimumab is associated with a high affinity FcγR polymorphism.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
32.4
作者：
Plitas, George;Konopacki, Catherine;Wu, Kenmin;Bos, Paula D.;Morrow, Monica;Putintseva, Ekaterina V.;Chudakov, Dmitriy M.;Rudensky, Alexander Y.
通讯作者：
Rudensky, Alexander Y.
影响因子：
51.1
作者：
Ribas, Antoni;Puzanov, Igor;Dummer, Reinhard;Schadendorf, Dirk;Hamid, Omid;Robert, Caroline;Hodi, F. Stephen;Schachter, Jacob;Pavlick, Anna C.;Lewis, Karl D.;Cranmer, Lee D.;Blank, Christian U.;O'Day, Steven J.;Ascierto, Paolo A.;Salama, April K. S.;Margolin, Kim A.;Loquai, Carmen;Eigentler, Thomas K.;Gangadhar, Tara C.;Carlino, Matteo S.;Agarwala, Sanjiv S.;Moschos, Stergios J.;Sosman, Jeffrey A.;Goldinger, Simone M.;Shapira-Frommer, Ronnie;Gonzalez, Rene;Kirkwood, John M.;Wolchok, Jedd D.;Eggermont, Alexander;Li, Xiaoyun Nicole;Zhou, Wei;Zernhelt, Adriane M.;Lis, Joy;Ebbinghaus, Scot;Kang, S. Peter;Daud, Adil
通讯作者：
Daud, Adil
影响因子：
64.8
作者：
DUNCAN, AR;WOOF, JM;WINTER, G
通讯作者：
WINTER, G
影响因子：
15.9
作者：
PARREN, PWHI;WARMERDAM, PAM;VANDEWINKEL, JGJ
通讯作者：
VANDEWINKEL, JGJ