The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse postinduction therapy in preclinical models of pediatric acute lymphoblastic leukemia.
The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse postinduction therapy in preclinical models of pediatric acute lymphoblastic leukemia.
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DOI：
10.1158/1078-0432.ccr-12-3613
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发表时间：
2013-04-01
期刊：
影响因子：
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通讯作者：
Lock RB
中科院分区：
文献类型：
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作者：
Carol H;Szymanska B;Evans K;Boehm I;Houghton PJ;Smith MA;Lock RB
复发或难治性儿童急性淋巴细胞白血病（ALL）仍然是儿童癌症死亡的主要原因。在这项研究中，我们评估了SAR3419（一种maytansinoid DM4和人源化抗cd19抗体的抗体-药物偶联物）对B细胞前体(BCP)-ALL和婴儿混合谱系白血病（MLL）异种移植物的疗效。在免疫缺陷（NOD/SCID）小鼠中，从患者直接移植的所有异种移植物被证实为全身性疾病。SAR3419作为单药和与长春新碱/地塞米松/ l -天冬酰胺酶（VXL）诱导型方案联合给药。实时评估白血病的进展和对治疗的反应，并根据临床环境建模的严格标准评估反应。SAR3419显著延缓4 / 4的CD19+ BCP-ALL和3 / 3的MLL-ALL异种移植物的进展，在除1例外的所有异种移植物中诱导客观反应，但对t系all异种移植物无效。异种移植组的相对表面CD19表达与白血病进展延迟和客观反应测量评分显著相关。SAR3419在大剂量（10倍）范围内对化疗耐药的BCP-ALL异种移植物也有显著的疗效，并且在两个高度化疗耐药的异种移植物中显著提高了vxl诱导的白血病进展延迟长达82天。在VXL诱导缓解后作为长期治疗，SAR3419可防止疾病复发到淋巴细胞和其他主要器官，但中枢神经系统除外。这些结果表明，将SAR3419纳入缓解诱导方案可能改善高危儿童和成人CD19+ ALL的预后。
Relapsed or refractory pediatric acute lymphoblastic leukemia (ALL) remains a major cause of death from cancer in children. In this study we evaluated the efficacy of SAR3419, an antibody-drug conjugate of the maytansinoid DM4 and a humanized anti-CD19 antibody, against B cell precursor (BCP)-ALL and infant mixed lineage leukemia (MLL) xenografts. ALL xenografts were established as systemic disease in immune-deficient (NOD/SCID) mice from direct patient explants. SAR3419 was administered as a single agent and in combination with an induction-type regimen of vincristine/dexamethasone/L-asparaginase (VXL). Leukemia progression and response to treatment were assessed in real-time, and responses were evaluated using strict criteria modeled after the clinical setting. SAR3419 significantly delayed the progression of four out of four CD19+ BCP-ALL and three out of three MLL-ALL xenografts, induced objective responses in all but one xenograft, but was ineffective against T-lineage ALL xenografts. Relative surface CD19 expression across the xenograft panel significantly correlated with leukemia progression delay and objective response measure scores. SAR3419 also exerted significant efficacy against chemoresistant BCP-ALL xenografts over a large (10-fold) dose range, and significantly enhanced VXL-induced leukemia progression delay in two highly chemoresistant xenografts by up to 82 days. When administered as protracted therapy following remission induction with VXL, SAR3419 prevented disease recurrence into hematolymphoid and other major organs with the notable exception of central nervous system involvement. These results suggest that incorporation of SAR3419 into remission induction protocols may improve the outcome for high-risk pediatric and adult CD19+ ALL.