Development of a Deimmunized Bispecific Immunotoxin dDT2219 against B-Cell Malignancies.
Development of a Deimmunized Bispecific Immunotoxin dDT2219 against B-Cell Malignancies.
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DOI：
10.3390/toxins10010032
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发表时间：
2018-01-06
期刊：
影响因子：
4.2
通讯作者：
Vallera DA
中科院分区：
文献类型：
--
作者：
Schmohl JU;Todhunter D;Taras E;Bachanova V;Vallera DA
Diphtheria toxin (DT) related targeted toxins are effective in cancer treatment, but efficacy diminishes in time because of their immunogenic potential and/or former vaccinations. In order to overcome this limitation for DT2219, a promising bispecific targeted toxin which targets CD19 and CD22, we deimmunized the DT moiety, and thereby developed an exciting improved drug (dDT2219) which still has the potential to sufficiently target B-cell malignancies but also limits clearance because of its reduced immunogenicity. The DT moiety was modified by inducing point mutations in prominent positions on the molecular surface. The new engineered dDT2219 was tested for activity, efficacy, and specificity using functional assays, proliferation assays, and flow cytometry. Furthermore, 12 samples of Chronic Lymphatic Leukemia (CLL) patients were used to assess binding. Immunogenicity was determined using a BALB/c mouse model. dDT2219 was efficient and specific against B-cell malignancies such as Bukitt-Lymphoma cell lines Daudi and Raji. dDT2219 showed specific binding on targets and on CLL samples. Intraperitoneal vaccination of immune competent mice showed that even after multiple administrations with increasing doses, induction of neutralizing antibodies was significantly lower in the dDT2219 treated animal group. The new dDT2219 combines potent anti-tumor cell activity with a reduced immunogenicity. With regard to the frequent development of neutralizing antibodies after multiple administrations with immunotoxins, dDT2219 shows promise to overcome this limitation and thus might maintain effectiveness even after multiple treatment cycles.
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从慢性淋巴细胞性白血病（CLL）患者中分离出恶性B细胞，以分析细胞增殖：验证一种适合多中心临床研究的简化方法。
影响因子：
2.7
作者：
Hayes GM;Busch R;Voogt J;Siah IM;Gee TA;Hellerstein MK;Chiorazzi N;Rai KR;Murphy EJ
通讯作者：
Murphy EJ
影响因子：
--
作者：
COLLIER, RJ
通讯作者：
COLLIER, RJ
DOI：
10.1158/1078-0432.ccr-14-2877
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bachanova V;Frankel AE;Cao Q;Lewis D;Grzywacz B;Verneris MR;Ustun C;Lazaryan A;McClune B;Warlick ED;Kantarjian H;Weisdorf DJ;Miller JS;Vallera DA
通讯作者：
Vallera DA
影响因子：
51.1
作者：
Kantarjian, Hagop;Thomas, Deborah;O'Brien, Susan
通讯作者：
O'Brien, Susan
影响因子：
3
作者：
Atassi, MZ;Dolimbek, BZ
通讯作者：
Dolimbek, BZ