lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

Smac Mimetic APG-1387 Has Synergistic Effect with anti-PD1 Antibody via Increasing NK Cells Recruitment by Inducing Multiple Cytokines from Tumor Cells

46 Pages Posted: 17 May 2019

See all articles by Wentao Pan

Wentao Pan

Sun Yat-Sen University (SYSU) - Department of Experimental Research; Suzhou Ascentage Pharma Inc.

Qiuyun Luo

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Douglas D. Fang

Suzhou Ascentage Pharma Inc.

Guangfeng Wang

Suzhou Ascentage Pharma Inc.

Mude Shi

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Jian Sun

Sun Yat-Sen University (SYSU) - Department of Experimental Research; Sun Yat-Sen University (SYSU) - Department of Clinical Research

Huimin Shen

Sun Yat-Sen University (SYSU) - First Affiliated Hospital

Zhenhai Lu

Sun Yat-Sen University (SYSU) - Department of Colorectal Surgery

Lin Zhang

Sun Yat-Sen University (SYSU) - Department of Experimental Research; Sun Yat-Sen University (SYSU) - Cancer Center

Xianglei Yan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Luping Yuan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Suna Zhou

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Hanjie Yi

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Yuxin Zhang

Sun Yat-Sen University (SYSU) - Department of Experimental Research

Mengxian Pan

Suzhou Ascentage Pharma Inc.

Yi-Fan Zhai

Suzhou Ascentage Pharma Inc.

Miao-Zhen Qiu

Sun Yat-Sen University (SYSU) - Department of Medical Oncology; Sun Yat-Sen University (SYSU) - Department of Experimental Research

Da-Jun Yang

Sun Yat-Sen University (SYSU) - Department of Experimental Research; Suzhou Ascentage Pharma Inc.

More...

Abstract

Background: Immune checkpoint inhibitor has got indication in various tumors, but the response rate was not satisfying. Identification of predictive biomarkers and novel combinations may enhance the response rate. Inhibitor of apoptosis proteins (IAP) ubiquitin-E3 ligase activity is involved in the regulation of immune responses mediated through NF-κB signaling. APG-1387 is a novel Smac-mimetic, which is quite safe and will not cause cytokine storm reaction in human. Based on these findings, we suspect that previous synergistic effect with checkpoint inhibitors of other IAPi may not suitable for APG-1387. In this study, we aim to explore the synergetic effect of APG-1387 with anti-PD1 antibody in preclinical setting.

Methods: We utilized syngeneic mouse models of ovarian cancer(ID8), colon cancer(MC38), melanoma(B16) and liver cancer(Hepa1-6) and assessed immune correlates, tumor growth, and survival following treatment with APG-1387 (0.2mg/kg, iv.) and anti-PD-1 antibody (5 mg/kg, ip.). In-vitro and in vivo cytokines release was measured by MSD V-PLEX. Findings: The synergistic effect of APG-1387 with anti-PD1 antibody was found in ID8 ovary and MC38 colon cancer models. APG-1387 combined with anti-PD-1 antibody significantly inhibited tumor growth and enhanced the survival rate of tumor-bearing animals. Moreover, we found that APG-1387 up-regulated tumor-infiltrating NK cells through IL-12 induced from tumor cells. Blocking IL-12p70 could abrogate the synergistic effect of APG1387 and anti-PD1 antibody in MC38 and ID8 models.

Interpretation: APG-1387 has potential to turn the cold tumor into hot one and recruited more NK cells in certain tumors.

Funding Statement: This study was supported by National Natural Science Foundation of China (NSFC: 81602066 and 81772587); Natural Science Foundation of Guangdong Province (2016A030313280 and 2018A030310260); The Sci-Tech Foundation of Guangdong Province (2018YJ021); The Medical Science Foundation of Guangdong Province (A2016023 and 2018102516469945). Natural Science Foundation of Guangdong Province (grant numbers 2014A030312015), Science and Technology Program of Guangdong (grant numbers 2015B020232008), Science and Technology Program of Guangzhou (grant numbers 15570006, 201508020250, 201510161726583, 201604020003), Guangdong Esophageal Cancer Institute Science and Technology Program (grant number M201809), CSCO-HengRui Oncology Research Fund (grant number Y-HR2018-184), the third outstanding young talents training plan and Medical Scientist program of Sun Yat-sen University cancer center, Medical Science and Technology Research Fund Project of Guangdong Province (grant number A2015003).

Declaration of Interests: Da-Jun Yang and Yifan Zhai have ownership interest (including patents) in Ascentage Pharma Group Corp. Limited. Wentao Pan, Douglas D. Fang, Guangfeng Wang and Mengxian Pan are employees of Ascentage Pharma Group Corp. Limited. No potential conflicts of interest were disclosed by the other authors.

Ethics Approval Statement: All experiments were performed with Animal Ethics Approval and conformed to regulatory standards set by the Sun Yat-Sen University Animal Ethics Committee.

Keywords: Smac Mimetic; APG-1387; Combination therapy; Immunotherapy; NK cells

Suggested Citation

Pan, Wentao and Luo, Qiuyun and Fang, Douglas D. and Wang, Guangfeng and Shi, Mude and Sun, Jian and Shen, Huimin and Lu, Zhenhai and Zhang, Lin and Yan, Xianglei and Yuan, Luping and Zhou, Suna and Yi, Hanjie and Zhang, Yuxin and Pan, Mengxian and Zhai, Yi-Fan and Qiu, Miao-Zhen and Yang, Da-Jun, Smac Mimetic APG-1387 Has Synergistic Effect with anti-PD1 Antibody via Increasing NK Cells Recruitment by Inducing Multiple Cytokines from Tumor Cells (May 14, 2019). Available at SSRN: https://ssrn.com/abstract=3388808 or http://dx.doi.org/10.2139/ssrn.3388808

Wentao Pan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Suzhou Ascentage Pharma Inc.

Jiangsu
China

Qiuyun Luo

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Douglas D. Fang

Suzhou Ascentage Pharma Inc.

Jiangsu
China

Guangfeng Wang

Suzhou Ascentage Pharma Inc.

Jiangsu
China

Mude Shi

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Jian Sun

Sun Yat-Sen University (SYSU) - Department of Experimental Research ( email )

651 Dongfeng Road East
Guangzhou, 510060
China

Sun Yat-Sen University (SYSU) - Department of Clinical Research ( email )

Guangzhou
China

Huimin Shen

Sun Yat-Sen University (SYSU) - First Affiliated Hospital

Guangzhou
China

Zhenhai Lu

Sun Yat-Sen University (SYSU) - Department of Colorectal Surgery ( email )

651 Dongfeng East Road
Guangzhou, 510060
United States

Lin Zhang

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Sun Yat-Sen University (SYSU) - Cancer Center

651 Dongfeng East Road
Guangzhou, 510060
China

Xianglei Yan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Luping Yuan

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Suna Zhou

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Hanjie Yi

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Yuxin Zhang

Sun Yat-Sen University (SYSU) - Department of Experimental Research

651 Dongfeng Road East
Guangzhou, 510060
China

Mengxian Pan

Suzhou Ascentage Pharma Inc.

Jiangsu
China

Yi-Fan Zhai

Suzhou Ascentage Pharma Inc. ( email )

Jiangsu
China

Miao-Zhen Qiu (Contact Author)

Sun Yat-Sen University (SYSU) - Department of Medical Oncology ( email )

651 Dongfeng Road East
Guangzhou, 510060
China

Sun Yat-Sen University (SYSU) - Department of Experimental Research ( email )

651 Dongfeng Road East
Guangzhou, 510060
China

Da-Jun Yang

Sun Yat-Sen University (SYSU) - Department of Experimental Research ( email )

651 Dongfeng Road East
Guangzhou, 510060
China

Suzhou Ascentage Pharma Inc. ( email )

Jiangsu
China

Click here to go to TheLancet.com

Paper statistics

Abstract Views
156
Downloads
5