Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain.
Improved pharmacokinetics of HIV-neutralizing VRC01-class antibodies achieved by reduction of net positive charge on variable domain.
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DOI：
10.1080/19420862.2023.2223350
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发表时间：
2023-01
期刊：
影响因子：
5.3
通讯作者：
Kwong, Peter D.
中科院分区：
文献类型：
--
作者：
Kwon, Young D.;Pegu, Amarendra;Yang, Eun Sung;Zhang, Baoshan;Bender, Michael F.;Asokan, Mangaiarkarasi;Liu, Qingbo;McKee, Krisha;Lin, Bob C.;Liu, Tracy;Louder, Mark K.;Rawi, Reda;Reveiz, Mateo;Schaub, Andrew J.;Shen, Chen-Hsiang;Doria-Rose, Nicole A.;Lusso, Paolo;Mascola, John R.;Kwong, Peter D.
关键词：
免疫球蛋白可变区的氨基酸组成已被观察到影响抗体药代动力学（PK）。在这里，我们试图通过降低VRC07-523LS和N6LS可变结构域的净正电荷来改善广泛的HIV - 1中和vrc01类抗体的PK。我们使用结构导向方法生成一组抗体变体，其中包含选定的Arg或Lys替换为Asp， Gln， Glu或Ser。在人fcrn转基因小鼠中，工程变异体对肝素的亲和力降低，多反应性降低，PK改善。一种型号，VRC07-523LS。v34具有三个电荷取代，其体内观察到的半衰期和估计的人体半衰期分别为10.8天和60天（VRC07-523LS为5.4天和38天），并保留了功能，在几何平均IC80 <1 μ g/mL时，中和了92%的208个菌株。另一个变种，N6LS。C49的体内半衰期和人体半衰期分别为14.5天和80天（N6LS为9.0天和44天），在几何平均IC80 <1 μ g/mL的条件下，中和了208株菌株的80%。由于Arg和Lys残基在人抗体中普遍存在，我们建议在框架区域用Asp、Gln、Glu或Ser替代选定的Arg或Lys，作为改善治疗性抗体PK的一般手段。
The amino-acid composition of the immunoglobulin variable region has been observed to impact antibody pharmacokinetics (PK). Here, we sought to improve the PK of the broad HIV−1-neutralizing VRC01-class antibodies, VRC07-523LS and N6LS, by reducing the net positive charge in their variable domains. We used a structure-guided approach to generate a panel of antibody variants incorporating select Arg or Lys substituted to Asp, Gln, Glu, or Ser. The engineered variants exhibited reduced affinity to heparin, reduced polyreactivity, and improved PK in human FcRn-transgenic mice. One variant, VRC07-523LS.v34, with three charge substitutions, had an observed in vivo half-life and an estimated human half-life of 10.8 and 60 days, respectively (versus 5.4 and 38 days for VRC07-523LS) and retained functionality, neutralizing 92% of a 208-strain panel at a geometric mean IC80 <1 µg/mL. Another variant, N6LS.C49, with two charge substitutions, had an observed in vivo half-life and an estimated human half-life of 14.5 and 80 days (versus 9.0 and 44 days for N6LS) and neutralized ~80% of 208 strains at a geometric mean IC80 <1 µg/mL. Since Arg and Lys residues are prevalent in human antibodies, we propose substitution of select Arg or Lys with Asp, Gln, Glu, or Ser in the framework region as a general means to improve PK of therapeutic antibodies.
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影响因子：
3.3
作者：
Gruell H;Klein F
通讯作者：
Klein F
抗体可变序列对细胞转运和血浆半衰期具有明显的影响。
影响因子：
5.8
作者：
Grevys A;Frick R;Mester S;Flem-Karlsen K;Nilsen J;Foss S;Sand KMK;Emrich T;Fischer JAA;Greiff V;Sandlie I;Schlothauer T;Andersen JT
通讯作者：
Andersen JT
影响因子：
2.4
作者：
Igawa, T.;Tsunoda, H.;Hattori, K.
通讯作者：
Hattori, K.
影响因子：
4.8
作者：
Hinton, PR;Johlfs, MG;Tsurushita, N
通讯作者：
Tsurushita, N
影响因子：
5.8
作者：
Dunbar, James;Deane, Charlotte M.
通讯作者：
Deane, Charlotte M.