In vivo engineered B cells secrete high titers of broadly neutralizing anti-HIV antibodies in mice.
In vivo engineered B cells secrete high titers of broadly neutralizing anti-HIV antibodies in mice.
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DOI：
10.1038/s41587-022-01328-9
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发表时间：
2022-08
影响因子：
46.9
通讯作者：
Barzel A
中科院分区：
文献类型：
--
作者：
Nahmad AD;Lazzarotto CR;Zelikson N;Kustin T;Tenuta M;Huang D;Reuveni I;Nataf D;Raviv Y;Horovitz-Fried M;Dotan I;Carmi Y;Rosin-Arbesfeld R;Nemazee D;Voss JE;Stern A;Tsai SQ;Barzel A
离体工程化以分泌广泛中和抗体（bNAb）的B细胞的移植在疾病模型中显示出功效。然而，这种方法的临床转化将需要专门的医疗中心，技术要求高的协议和供体细胞和受体的MHC相容性。在这里，我们报告了使用两种腺相关病毒载体的体内B细胞工程，其中一种编码saCas 9，另一种编码抗HIV bNA B的3BNC 117。在将载体静脉注射到小鼠中后，我们观察到B细胞的成功编辑，导致记忆保留和bNA B分泌，中和滴度高达6.8 μg/mL。我们观察到最小的CRISPR-Cas9脱靶切割，如通过无偏CHANGE-Seq分析检测的，而通过从B细胞特异性启动子表达saCas 9减少了不期望的组织中的中靶切割。体内B细胞工程化以表达治疗性抗体是一种安全、有效和可扩展的方法，其不仅可适用于感染性疾病，而且可用于治疗非传染性病症，如癌症和自身免疫性疾病。
Transplantation of B cells engineered ex vivo to secrete broadly neutralizing antibodies (bNAbs) has shown efficacy in disease models. However, clinical translation of this approach would require specialized medical centers, technically demanding protocols and MHC compatibility of donor cells and recipients. Here, we report in vivo B cell engineering using two adeno-associated viral vectors, with one coding for saCas9 and the other for 3BNC117, an anti-HIV bNAb. After intravenously injecting the vectors into mice, we observe successful editing of B cells leading to memory retention and bNAb secretion at neutralizing titers of up to 6.8 μg/mL. We observed minimal CRISPR-Cas9 off-target cleavage as detected by unbiased CHANGE-Seq analysis, whereas on-target cleavage in undesired tissues is reduced by expressing saCas9 from a B cell-specific promoter. In vivo B cell engineering to express therapeutic antibodies is a safe, potent and scalable method, which may be applicable not only to infectious diseases but also in the treatment of non-communicable conditions, such as cancer and autoimmune disease.
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影响因子：
64.8
作者：
Barzel, A.;Paulk, N. K.;Shi, Y.;Huang, Y.;Chu, K.;Zhang, F.;Valdmanis, P. N.;Spector, L. P.;Porteus, M. H.;Gaensler, K. M.;Kay, M. A.
通讯作者：
Kay, M. A.
影响因子：
6
作者：
Gong X;Yan H;Ma J;Zhu Z;Zhang S;Xu W;Huang J;Qiu X
通讯作者：
Qiu X
影响因子：
46.9
作者：
Ferrari S;Jacob A;Beretta S;Unali G;Albano L;Vavassori V;Cittaro D;Lazarevic D;Brombin C;Cugnata F;Kajaste-Rudnitski A;Merelli I;Genovese P;Naldini L
通讯作者：
Naldini L
影响因子：
16.6
作者：
Huang D;Tran JT;Olson A;Vollbrecht T;Tenuta M;Guryleva MV;Fuller RP;Schiffner T;Abadejos JR;Couvrette L;Blane TR;Saye K;Li W;Landais E;Gonzalez-Martin A;Schief W;Murrell B;Burton DR;Nemazee D;Voss JE
通讯作者：
Voss JE
影响因子：
10.6
作者：
Busch, Svenja;Talamini, Marina;Fuchs, Tina
通讯作者：
Fuchs, Tina