New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models.
New anti-IL-7Rα monoclonal antibodies show efficacy against T cell acute lymphoblastic leukemia in pre-clinical models.
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DOI：
10.1038/s41375-019-0531-8
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发表时间：
2020-01
期刊：
影响因子：
11.4
通讯作者：
Durum SK
中科院分区：
文献类型：
--
作者：
Hixon JA;Andrews C;Kashi L;Kohnhorst CL;Senkevitch E;Czarra K;Barata JT;Li W;Schneider JP;Walsh STR;Durum SK
儿童T细胞急性淋巴细胞性白血病(T-ALL)细胞常含有白细胞介素7(IL-7)受体途径的突变，或对IL-7本身有反应。为了靶向T-ALL细胞上的IL-7受体，制备了抗人IL-7Rα链的小鼠单抗，并与人Ig G1恒定区嵌合。晶体结构表明，这两株单抗结合了不同的IL-7Rα表位。单抗介导的抗体依赖的细胞介导的细胞毒(ADCC)的患者来源的异种(PDX)T-ALL细胞，这是由两个单抗联合改善。在体内，单抗通过ADCC依赖和独立的机制对微小残留和既往疾病显示出治疗效果。化疗后复发的PDX T-ALL细胞显示IL-7Rα升高，单抗治疗对复发疾病有效，建议在复发T-ALL患者或化疗无效的患者中使用抗IL7Rα单抗。
Pediatric T cell acute lymphoblastic leukemia (T-ALL) cells frequently contain mutations in the interleukin-7 (IL-7) receptor pathway or respond to IL-7 itself. To target the IL-7 receptor on T-ALL cells, murine monoclonal antibodies (MAbs) were developed against the human IL-7Rα chain and chimerized with human IgG1 constant regions. Crystal structures demonstrate that the two MAbs bound different IL-7Rα epitopes. The MAbs mediated antibody-dependent cell-mediated cytotoxicity (ADCC) against patient-derived xenograft (PDX) T-ALL cells, which was improved by combining two MAbs. In vivo, the MAbs showed therapeutic efficacy via ADCC-dependent and independent mechanisms in minimal residual and established disease. PDX T-ALL cells that relapsed following a course of chemotherapy displayed elevated IL-7Rα, and MAb treatment is effective against relapsing disease, suggesting the use of anti-IL7Rα MAbs in relapsed T-ALL patients or patients that do not respond to chemotherapy.
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影响因子：
50.3
作者：
Roberts KG;Morin RD;Zhang J;Hirst M;Zhao Y;Su X;Chen SC;Payne-Turner D;Churchman ML;Harvey RC;Chen X;Kasap C;Yan C;Becksfort J;Finney RP;Teachey DT;Maude SL;Tse K;Moore R;Jones S;Mungall K;Birol I;Edmonson MN;Hu Y;Buetow KE;Chen IM;Carroll WL;Wei L;Ma J;Kleppe M;Levine RL;Garcia-Manero G;Larsen E;Shah NP;Devidas M;Reaman G;Smith M;Paugh SW;Evans WE;Grupp SA;Jeha S;Pui CH;Gerhard DS;Downing JR;Willman CL;Loh M;Hunger SP;Marra MA;Mullighan CG
通讯作者：
Mullighan CG
影响因子：
20.3
作者：
Cramer, Sarah D.;Aplan, Peter D.;Durum, Scott K.
通讯作者：
Durum, Scott K.
影响因子：
5.2
作者：
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通讯作者：
You, Jueng Soo
影响因子：
20.3
作者：
Karawajew, L;Ruppert, V;Ludwig, WD
通讯作者：
Ludwig, WD
影响因子：
20.3
作者：
Maude, Shannon L.;Dolai, Sibasish;Teachey, David T.
通讯作者：
Teachey, David T.