Two Distinct Lysosomal Targeting Strategies Afford Trojan Horse Antibodies With Pan-Filovirus Activity.
Two Distinct Lysosomal Targeting Strategies Afford Trojan Horse Antibodies With Pan-Filovirus Activity.
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DOI：
10.3389/fimmu.2021.729851
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发表时间：
2021
影响因子：
7.3
通讯作者：
Chandran K
中科院分区：
文献类型：
--
作者：
Wirchnianski AS;Wec AZ;Nyakatura EK;Herbert AS;Slough MM;Kuehne AI;Mittler E;Jangra RK;Teruya J;Dye JM;Lai JR;Chandran K
丝状病毒科（丝状病毒）中的多种病原体与高致死性疾病的散发性人类暴发有关，而其他病原体，包括最近鉴定的几种病原体，具有很强的人畜共患病潜力。尽管病毒糖蛋白（GP）特异性单克隆抗体已显示出对丝状病毒病的治疗效用，但目前FDA批准的分子缺乏抗病毒广度。广泛中和抗体的开发受到丝状病毒GP之间的高序列差异和伴随丝状病毒进入的复杂GP蛋白水解切割级联的挑战。尽管GP的抗原表面存在这种变异性，但所有丝状病毒都有一个共同的亲和性位点--通用丝状病毒进入受体尼曼-匹克C1（NPC 1）的结合位点。不幸的是，该位点在细胞外GP中被屏蔽，并且仅通过晚期内体和溶酶体中的宿主蛋白酶的蛋白水解切割而未被发现，所述晚期内体和溶酶体通常是抗体无法接近的。为了克服这一障碍，我们以前开发了一种“特洛伊木马”治疗方法，其中工程双特异性抗体（bsAb）coopt病毒颗粒，以提供GP：NPC 1相互作用阻断抗体到其内/溶酶体的作用位点。这种方法提供了针对埃博拉病毒属成员的广泛保护，但不能中和更多不同的丝状病毒。在这里，我们描述了下一代特洛伊木马bsAb的目标内/溶酶体GP：NPC 1接口与泛丝状病毒的宽度，利用保守的和广泛表达的宿主阳离子非依赖性甘露糖-6-磷酸受体的细胞内交付。我们的工作突出了开发单一疗法的新途径，可以保护所有已知和新出现的丝状病毒。
Multiple agents in the family Filoviridae (filoviruses) are associated with sporadic human outbreaks of highly lethal disease, while others, including several recently identified agents, possess strong zoonotic potential. Although viral glycoprotein (GP)-specific monoclonal antibodies have demonstrated therapeutic utility against filovirus disease, currently FDA-approved molecules lack antiviral breadth. The development of broadly neutralizing antibodies has been challenged by the high sequence divergence among filovirus GPs and the complex GP proteolytic cleavage cascade that accompanies filovirus entry. Despite this variability in the antigenic surface of GP, all filoviruses share a site of vulnerability—the binding site for the universal filovirus entry receptor, Niemann-Pick C1 (NPC1). Unfortunately, this site is shielded in extracellular GP and only uncovered by proteolytic cleavage by host proteases in late endosomes and lysosomes, which are generally inaccessible to antibodies. To overcome this obstacle, we previously developed a ‘Trojan horse’ therapeutic approach in which engineered bispecific antibodies (bsAbs) coopt viral particles to deliver GP:NPC1 interaction-blocking antibodies to their endo/lysosomal sites of action. This approach afforded broad protection against members of the genus Ebolavirus but could not neutralize more divergent filoviruses. Here, we describe next-generation Trojan horse bsAbs that target the endo/lysosomal GP:NPC1 interface with pan-filovirus breadth by exploiting the conserved and widely expressed host cation-independent mannose-6-phosphate receptor for intracellular delivery. Our work highlights a new avenue for the development of single therapeutics protecting against all known and newly emerging filoviruses.
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影响因子：
32.4
作者：
Gilchuk P;Kuzmina N;Ilinykh PA;Huang K;Gunn BM;Bryan A;Davidson E;Doranz BJ;Turner HL;Fusco ML;Bramble MS;Hoff NA;Binshtein E;Kose N;Flyak AI;Flinko R;Orlandi C;Carnahan R;Parrish EH;Sevy AM;Bombardi RG;Singh PK;Mukadi P;Muyembe-Tamfum JJ;Ohi MD;Saphire EO;Lewis GK;Alter G;Ward AB;Rimoin AW;Bukreyev A;Crowe JE Jr
通讯作者：
Crowe JE Jr
影响因子：
64.5
作者：
Flyak AI;Shen X;Murin CD;Turner HL;David JA;Fusco ML;Lampley R;Kose N;Ilinykh PA;Kuzmina N;Branchizio A;King H;Brown L;Bryan C;Davidson E;Doranz BJ;Slaughter JC;Sapparapu G;Klages C;Ksiazek TG;Saphire EO;Ward AB;Bukreyev A;Crowe JE Jr
通讯作者：
Crowe JE Jr
影响因子：
64.8
作者：
Cote, Marceline;Misasi, John;Ren, Tao;Bruchez, Anna;Lee, Kyungae;Filone, Claire Marie;Hensley, Lisa;Li, Qi;Ory, Daniel;Chandran, Kartik;Cunningham, James
通讯作者：
Cunningham, James
影响因子：
4.6
作者：
Frei JC;Nyakatura EK;Zak SE;Bakken RR;Chandran K;Dye JM;Lai JR
通讯作者：
Lai JR
影响因子：
28.3
作者：
Goldstein T;Anthony SJ;Gbakima A;Bird BH;Bangura J;Tremeau-Bravard A;Belaganahalli MN;Wells HL;Dhanota JK;Liang E;Grodus M;Jangra RK;DeJesus VA;Lasso G;Smith BR;Jambai A;Kamara BO;Kamara S;Bangura W;Monagin C;Shapira S;Johnson CK;Saylors K;Rubin EM;Chandran K;Lipkin WI;Mazet JAK
通讯作者：
Mazet JAK