Identification of Anti-gp41 Monoclonal Antibodies That Effectively Target Cytotoxic Immunoconjugates to Cells Infected with Human Immunodeficiency Virus, Type 1.
Identification of Anti-gp41 Monoclonal Antibodies That Effectively Target Cytotoxic Immunoconjugates to Cells Infected with Human Immunodeficiency Virus, Type 1.
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DOI：
10.3390/vaccines11040829
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发表时间：
2023-04-12
期刊：
影响因子：
7.8
通讯作者：
Pincus SH
中科院分区：
文献类型：
--
作者：
Klug G;Cole FM;Hicar MD;Watt C;Peters T;Pincus SH
我们正在开发针对人类免疫缺陷病毒 1 型 (HIV) 包膜蛋白 (Env) 的细胞毒性免疫偶联物 (CIC)，以清除病毒感染的持续储存库。我们之前研究过多种单克隆抗体 (mAb) 将 CIC 递送至 HIV 感染细胞的能力。我们发现，靶向 Env 跨膜 gp41 结构域的 CIC 最有效，部分原因是在可溶性 CD4 存在的情况下，它们的杀伤力增强。 mAb 递送 CIC 的能力与其中和或介导 Ab 依赖性细胞毒性的能力无关。在当前的研究中，我们寻求定义最有效的抗 gp41 mAb，用于将 CIC 递送至 HIV 感染的细胞。为此，我们评估了一组人类抗 gp41 mAb 结合和杀死两种不同的 Env 表达细胞系的能力：持续感染的 H9/NL4-3 和组成型转染的 HEK293/92UG。我们测量了每种 mAb 在存在和不存在可溶性 CD4 的情况下的结合和细胞毒性。我们发现针对 gp41 免疫显性螺旋-环-螺旋区域 (ID-loop) 的 mAb 最有效，而针对融合肽、gp120/gp41 界面和膜近端外部区域 (MPER) 的中和 mAb 在递送 CIC 方面相对无效。抗原暴露和杀伤活性之间只有微弱的相关性。结果表明，提供有效 IC 和中和的能力是 mAb 的不同功能。
We are developing cytotoxic immunoconjugates (CICs) targeting the envelope protein (Env) of the Human Immunodeficiency Virus, type 1 (HIV) to purge the persistent reservoirs of viral infection. We have previously studied the ability of multiple monoclonal antibodies (mAbs) to deliver CICs to an HIV-infected cell. We have found that CICs targeted to the membrane-spanning gp41 domain of Env are most efficacious, in part because their killing is enhanced in the presence of soluble CD4. The ability of a mAb to deliver a CIC does not correlate with its ability to neutralize nor mediate Ab-dependent cellular cytotoxicity. In the current study, we seek to define the most effective anti-gp41 mAbs for delivering CICs to HIV-infected cells. To do this, we have evaluated a panel of human anti-gp41 mAbs for their ability to bind and kill two different Env-expressing cell lines: persistently infected H9/NL4-3 and constitutively transfected HEK293/92UG. We measured the binding and cytotoxicity of each mAb in the presence and absence of soluble CD4. We found that mAbs to the immunodominant helix-loop-helix region (ID-loop) of gp41 are most effective, whereas neutralizing mAbs to the fusion peptide, gp120/gp41 interface, and the membrane proximal external region (MPER) are relatively ineffective at delivering CICs. There was only a weak correlation between antigen exposure and killing activity. The results show that the ability to deliver an effective IC and neutralization are distinct functions of mAbs.
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影响因子：
7.8
作者：
Pincus SH;Craig RB;Weachter L;LaBranche CC;Nabi R;Watt C;Raymond M;Peters T;Song K;Maresh GA;Montefiori DC;Kozlowski PA
通讯作者：
Kozlowski PA
影响因子：
16.6
作者：
Bruel T;Guivel-Benhassine F;Amraoui S;Malbec M;Richard L;Bourdic K;Donahue DA;Lorin V;Casartelli N;Noël N;Lambotte O;Mouquet H;Schwartz O
通讯作者：
Schwartz O
影响因子：
32.4
作者：
Brooks, DG;Hamer, DH;Zack, JA
通讯作者：
Zack, JA
影响因子：
1.5
作者：
Fang, H;Pincus, S
通讯作者：
Pincus, S
影响因子：
17.1
作者：
Balibar, Carl J.;Klein, Daniel J.;Converso, Antonella
通讯作者：
Converso, Antonella