McLeod Robbie L, Angagaw Minilik H, Baral Toya Nath, Liu Liming, Moniz Raymond Joseph, Laskey Jason, Hsieh SuChun, Lee Mike, Han Jin-Hwan, Issafras Hassan, Javaid Sarah, Loboda Andrey, Sadekova Svetlana, O'Connor Joann A, Tse Archie, Punnonen Juha
Merck & Co., Inc., Boston, MA, USA.
Merck & Co., Inc., Kenilworth, NJ, USA.
Oncotarget. 2018 Oct 2;9(77):34459-34470. doi: 10.18632/oncotarget.26108.
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been reported to mediate both tumorigenic and anti-tumor effects . Blockade of the CEACAM1 signaling pathway has recently been implicated as a novel mechanism for cancer immunotherapy. CC1, a mouse anti-CEACAM1 monoclonal antibody (mAb), has been widely used as a pharmacological tool in preclinical studies to inform on CEACAM1 pathway biology although limited data are available on its CEACAM1 blocking characteristics or pharmacodynamic-pharmacokinetic profiles. We sought to investigate CEACAM1 expression on mouse tumor and immune cells, characterize CC1 mAb binding, and evaluate CC1 in syngeneic mouse oncology models as a monotherapy and in combination with an anti-PD-1 mAb. CEACAM1 expression was observed at high levels on neutrophils, NK cells and myeloid-derived suppressor cells (MDSCs), while the expression on tumor-infiltrating CD8+ T cells was low. Unexpectedly, rather than blocking, CC1 facilitated binding of soluble CEACAM1 to CEACAM1 expressing cells. No anti-tumor effects were observed in CT26, MBT2 or A20 models when tested up to 30 mg/kg dose, a dose that was estimated to achieve >90% target engagement . Taken together, tumor infiltrating CD8+ T cells express low levels of CEACAM1 and CC1 Ab mediates no or minimal anti-tumor effects , as a monotherapy or in combination with anti-PD-1 treatment.
癌胚抗原相关细胞黏附分子1（CEACAM1）已被报道可介导致瘤和抗肿瘤作用。最近，CEACAM1信号通路的阻断被认为是癌症免疫治疗的一种新机制。CC1是一种小鼠抗CEACAM1单克隆抗体（mAb），尽管关于其CEACAM1阻断特性或药效学-药代动力学特征的数据有限，但它已在临床前研究中广泛用作药理学工具，以了解CEACAM1通路生物学。我们试图研究CEACAM1在小鼠肿瘤和免疫细胞上的表达，表征CC1 mAb的结合情况，并在同基因小鼠肿瘤模型中评估CC1作为单一疗法以及与抗PD-1 mAb联合使用时的效果。在中性粒细胞、自然杀伤细胞（NK细胞）和髓源性抑制细胞（MDSC）上观察到高水平的CEACAM1表达，而肿瘤浸润性CD8 + T细胞上的表达较低。出乎意料的是，CC1并未起到阻断作用，而是促进了可溶性CEACAM1与表达CEACAM1的细胞的结合。在CT26、MBT2或A20模型中，当测试剂量高达30 mg/kg时（据估计该剂量可实现>90%的靶点结合），未观察到抗肿瘤作用。综上所述，肿瘤浸润性CD8 + T细胞表达低水平的CEACAM1，CC1抗体作为单一疗法或与抗PD-1治疗联合使用时，均未介导或仅介导极小的抗肿瘤作用。
