Tumor-targeting anti-EGFR x anti-PD1 bispecific antibody inhibits EGFR-overexpressing tumor growth by combining EGFR blockade and immune activation with direct tumor cell killing.
Tumor-targeting anti-EGFR x anti-PD1 bispecific antibody inhibits EGFR-overexpressing tumor growth by combining EGFR blockade and immune activation with direct tumor cell killing.
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DOI：
10.1016/j.tranon.2020.100916
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发表时间：
2021-01
影响因子：
5
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Li L;Deng L;Meng X;Gu C;Meng L;Li K;Zhang X;Meng Y;Xu W;Zhao L;Chen J;Zhu Z;Huang H
抗pd1 x抗egfr双特异性抗体（BsAb）在体外表现出与亲本单抗相当的生物活性，并且在体内显示出与单抗相当的两臂抗肿瘤功效。抗pd1 x抗egfr双特异性抗体（BsAb）对癌细胞保留完整的ADCC，但对T细胞不保留ADCC。因此，BsAb能够通过ADCC杀死肿瘤细胞，同时保留T细胞进行T细胞诱导的抗肿瘤免疫。与西妥昔单抗联合抗pd1单抗609A相比，抗pd1 x抗egfr双特异性抗体（BsAb）在PBMC存在下表现出更强的肿瘤细胞杀伤作用。我们开发了一种结合常规靶向治疗和免疫检查点阻断的策略，使用肿瘤靶向双特异性抗体（BsAb）来治疗实体瘤。BsAb被设计用于同时结合肿瘤相关抗原、表皮生长因子受体（EGFR）和程序性细胞死亡蛋白1 （PD1）。除了通过EGFR抑制其直接抗肿瘤活性外，BsAb还介导有效的抗体依赖性细胞毒性（ADCC），并通过阻断PD1与其对偶物程序性细胞死亡配体1 （PDL1）的相互作用激活T细胞抗肿瘤免疫。此外，在PBMC存在的情况下，BsAb表现出一种有效的直接杀伤肿瘤细胞的活性，很可能是通过激活T细胞，同时使T细胞与肿瘤细胞物理结合。综上所述，我们在这里阐述了一种设计和生产新型bsab的新策略，该策略通过直接抑制肿瘤生长和通过肿瘤靶向免疫检查点阻断激活T细胞来增强治疗效果。
The anti-PD1 x anti-EGFR bispecific antibody (BsAb) exhibited all in-vitro bioactivities comparable to that of the parental mAbs and showed anti-tumor efficacies of each of the two arms on par with the mAbs in-vivo. The anti-PD1 x anti-EGFR bispecific antibody (BsAb) retained full ADCC towards cancer cells but not to T cells. Thus the BsAb is capable of killing tumor cells via ADCC while sparing T cells for T cell-induced anti-tumor immunity. The anti-PD1 x anti-EGFR bispecific antibody (BsAb) exhibited significantly stronger tumor cell killing effects in the presence of PBMC relative to that of combination of cetuximab with an anti-PD1 mAb, 609A. We developed a strategy to combine conventional targeted therapy with immune checkpoint blockade using a tumor-targeting bispecific antibody (BsAb) to treat solid tumors. The BsAb was designed to simultaneously engage a tumor-associated antigen, epidermal growth factor receptor (EGFR), and programed cell death protein 1 (PD1). In addition to its direct anti-tumor activity via EGFR inhibition, the BsAb mediated efficient antibody-dependent cellular cytotoxicity (ADCC) and activated T cell antitumor im munity through blockade of PD1 from interacting with its counterpart, programed cell death ligand 1 (PDL1). Further, the BsAb exhibited a potent direct tumor cell killing activity in the presence of PBMC, most likely, via activating and, at the same time, physically engaging T cells with tumor cells. Taken together, we here illustrate a new strategy in the design and production of novel BsAbs with enhanced therapeutic efficacy through both direct tumor growth inhibition and T cell activation via tumor-targeted immune checkpoint blockade.
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影响因子：
50.3
作者：
Li J;Stagg NJ;Johnston J;Harris MJ;Menzies SA;DiCara D;Clark V;Hristopoulos M;Cook R;Slaga D;Nakamura R;McCarty L;Sukumaran S;Luis E;Ye Z;Wu TD;Sumiyoshi T;Danilenko D;Lee GY;Totpal K;Ellerman D;Hötzel I;James JR;Junttila TT
通讯作者：
Junttila TT
影响因子：
3.7
作者：
Ma W;Concha-Benavente F;Santegoets SJAM;Welters MJP;Ehsan I;Ferris RL;van der Burg SH
通讯作者：
van der Burg SH
影响因子：
28.2
作者：
Grasso CS;Giannakis M;Wells DK;Hamada T;Mu XJ;Quist M;Nowak JA;Nishihara R;Qian ZR;Inamura K;Morikawa T;Nosho K;Abril-Rodriguez G;Connolly C;Escuin-Ordinas H;Geybels MS;Grady WM;Hsu L;Hu-Lieskovan S;Huyghe JR;Kim YJ;Krystofinski P;Leiserson MDM;Montoya DJ;Nadel BB;Pellegrini M;Pritchard CC;Puig-Saus C;Quist EH;Raphael BJ;Salipante SJ;Shin DS;Shinbrot E;Shirts B;Shukla S;Stanford JL;Sun W;Tsoi J;Upfill-Brown A;Wheeler DA;Wu CJ;Yu M;Zaidi SH;Zaretsky JM;Gabriel SB;Lander ES;Garraway LA;Hudson TJ;Fuchs CS;Ribas A;Ogino S;Peters U
通讯作者：
Peters U
影响因子：
56.9
作者：
ANDERSON, D;KOCH, CA;PAWSON, T
通讯作者：
PAWSON, T
影响因子：
7.2
作者：
Koopmans I;Hendriks D;Samplonius DF;van Ginkel RJ;Heskamp S;Wierstra PJ;Bremer E;Helfrich W
通讯作者：
Helfrich W