Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition.
Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition.
复制标题
DOI：
10.1038/s41401-021-00683-8
复制
发表时间：
2022-03
影响因子：
8.2
通讯作者：
Huang HM
中科院分区：
文献类型：
--
作者：
Gu CL;Zhu HX;Deng L;Meng XQ;Li K;Xu W;Zhao L;Liu YQ;Zhu ZP;Huang HM
免疫检查点阻断在多种癌症适应症中显示出显著的临床益处，但许多患者要么是难治性的，要么随着时间的推移对治疗产生耐药性。HER 2/neu癌基因在浸润性乳腺癌患者中的过度表达与更高的侵袭性疾病和不良预后相关。抗HER 2单抗，如曲妥珠单抗，目前是HER 2过表达癌症的标准治疗，但缓解率低于30%，患者通常在一年内复发。在这项研究中，我们开发了一种同时靶向PD 1和HER 2的双特异性抗体（BsAb），试图将联合收割机HER 2靶向治疗与免疫检查点阻断相结合，用于治疗HER 2阳性实体瘤。通过柔性肽接头将scFv（抗PD 1）与IgG（曲妥珠单抗）的效应子功能性Fc融合来构建BsAb。我们发现，BsAb结合人HER 2和PD 1具有高亲和力（EC 50值分别为0.2和0.14 nM），并在体外和体内表现出有效的抗肿瘤活性。此外，我们证明了BsAb表现出HER 2和PD 1阻断活性，并且通过抗体依赖性细胞毒性有效杀死HER 2阳性肿瘤细胞。此外，BsAb可以将HER 2阳性肿瘤细胞与T细胞交联以形成PD 1免疫突触，其指导肿瘤细胞杀伤而不需要抗原呈递。因此，BsAb是治疗晚期转移性HER 2阳性癌症的新的有前途的方法。
Immune checkpoint blockade has shown significant clinical benefit in multiple cancer indications, but many patients are either refractory or become resistant to the treatment over time. HER2/neu oncogene overexpressed in invasive breast cancer patients associates with more aggressive diseases and poor prognosis. Anti-HER2 mAbs, such as trastuzumab, are currently the standard of care for HER2-overexpressing cancers, but the response rates are below 30% and patients generally suffer relapse within a year. In this study we developed a bispecific antibody (BsAb) simultaneously targeting both PD1 and HER2 in an attempt to combine HER2-targeted therapy with immune checkpoint blockade for treating HER2-positive solid tumors. The BsAb was constructed by fusing scFvs (anti-PD1) with the effector-functional Fc of an IgG (trastuzumab) via a flexible peptide linker. We showed that the BsAb bound to human HER2 and PD1 with high affinities (EC50 values were 0.2 and 0.14 nM, respectively), and exhibited potent antitumor activities in vitro and in vivo. Furthermore, we demonstrated that the BsAb exhibited both HER2 and PD1 blockade activities and was effective in killing HER2-positive tumor cells via antibody-dependent cellular cytotoxicity. In addition, the BsAb could crosslink HER2-positive tumor cells with T cells to form PD1 immunological synapses that directed tumor cell killing without the need of antigen presentation. Thus, the BsAb is a new promising approach for treating late-stage metastatic HER2-positive cancers.
登录
查看更多内容
影响因子：
9.7
作者：
Chaganty BKR;Qiu S;Gest A;Lu Y;Ivan C;Calin GA;Weiner LM;Fan Z
通讯作者：
Fan Z
影响因子：
5
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
通讯作者：
Huang H
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
靶向双重肿瘤相关抗原在癌症治疗中的双特异性抗体。
影响因子：
3.6
作者：
Huang S;van Duijnhoven SMJ;Sijts AJAM;van Elsas A
通讯作者：
van Elsas A
影响因子：
--
作者：
de Melo Gagliato D;Jardim DL;Marchesi MS;Hortobagyi GN
通讯作者：
Hortobagyi GN