|Table of Contents|

Siglec-15×CD3 bispecific antibody inhibits the growth of colorectal cancer cells by mediating T cell antitumor immunity

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2023 04
Page:
638-643
Research Field:
Publishing date:

Info

Title:
Siglec-15×CD3 bispecific antibody inhibits the growth of colorectal cancer cells by mediating T cell antitumor immunity
Author(s):
WU Yuanhao1 ; HUANG Ping1 ; LI Laichun2
1.Department of Anorectal Surgery;2.Department of Nuclear Medicine,Hainan Provincial People's Hospital,Hainan Haikou 570311,China.
Keywords:
colorectal cancer; Siglec-15; BiTE; antibody; T cells
PACS:
R735.3
DOI:
10.3969/j.issn.1672-4992.2023.04.008
Abstract:
Objective:To investigate whether Siglec-15×CD3 bispecific T-cell engager (BiTE) can mediate the antitumor immune response of T cells in vitro and in vivo and inhibit the growth of colorectal cancer cells.Methods:Expi293TM expression system was used to express 32A1-IgG and 32A1-BiTE proteins.The binding of 32A1-IgG and 32A1-BiTE to target protein was detected by ELISA.Flow cytometry was used to detect the expression of Siglec-15 in colorectal cancer cell lines.LDH assay was used to detect the cytotoxicity of 32A1-BiTE mediated T cells against target cells.The inhibitory effect of 32A1-BiTE on tumor was detected in mouse transplanted tumor model.Immunohistochemical method was used to detect the content of tumor infiltrating CD3+ T cells.Flow cytometry was used to detect the secretion of GzmB in tumor infiltrating CD8+ T cells.Results:The purity of 32A1-IgG and 32A1-BiTE proteins was greater than 95%.32A1-BiTE had strong binding ability to Siglec-15 and CD3.Colorectal cancer cell lines SW480,HCT116 and HT-29 showed high expression of Siglec-15.32A1-BiTE can mediate T cell cytotoxicity to target cells in a dose-dependent manner.32A1-BiTE can effectively inhibit the growth of SW480 cells in mice (P＜0.000 1),increase the number of CD3+ T cells infiltrated by tumor (P＜0.000 1),and significantly increase the proportion of CD8+ T cells (P＜0.01) and their GzmB secretion level (P＜0.000 1).Conclusion:32A1-BiTE can mediate the antitumor immune response of T cells in vivo and in vitro,and inhibit the growth of colorectal cancer cells,which may be a promising drug for the treatment of colorectal cancer.

References:

[1] BECA JM,DAI WF,PATAKY RE,et al.Real-world safety of bevacizumab with first-line combination chemotherapy in patients with metastatic colorectal cancer:population-based retrospective cohort studies in three Canadian provinces［J］.Clin Oncol (R Coll Radiol),2022,34(1):e7-e17.
[2] FOROUGHI S,WONG HL,TIE J,et al.Characteristics and outcomes of participants in colorectal cancer biomarker trials versus a real-world cohort［J］.Acta Oncol,2021,60(4):482-490.
[3] ONYEAGHALA G,LINTELMANN AK,JOSHU CE,et al.Adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention guidelines and colorectal cancer incidence among African Americans and whites:The Atherosclerosis Risk in Communities study［J］.Cancer,2020,126(5):1041-1050.
[4] PATEL AK,BARGHOUT V,YENIKOMSHIAN MA,et al.Real-world adherence in patients with metastatic colorectal cancer treated with trifluridine plus tipiracil or regorafenib［J］.Oncologist,2020,25(1):e75-e84.
[5] ROMANO FJ,BARBATO C,BIGLIETTO M,et al.Folinic acid in colorectal cancer:esquire or fellow knight? Real-world results from a mono institutional,retrospective study［J］.Oncotarget,2021,12(3):221-229.
[6] FLEMMING A.Cancer:Antitumour responses with more BiTE［J］.Nat Rev Drug Discov,2015,14(11):749.
[7] KLINGER M,BENJAMIN J,KISCHEL R,et al.Harnessing T cells to fight cancer with BiTE(R) antibody constructs-past developments and future directions［J］.Immunol Rev,2016,270(1):193-208.
[8] ZHU M,WU B,BRANDL C,et al.Blinatumomab,a bispecific T-cell engager(BiTE) for CD-19 Targeted cancer immunotherapy:clinical pharmacology and its implications［J］,Clin Pharmacokinet,2016,55(10):1271-1288.
[9] RASHID S,SONG D,YUAN J,et al.Molecular structure,expression,and the emerging role of Siglec-15 in skeletal biology and cancer［J］.J Cell Physiol,2022,237(3):1711-1719.
[10] SUN J,LU Q,SANMAMED MF,et al.Siglec-15 as an emerging target for next-generation cancer immunotherapy［J］.Clin Cancer Res,2021,27(3):680-688.
[11] ANGATA T.Siglec-15:a potential regulator of osteoporosis,cancer,and infectious diseases［J］.J Biomed Sci,2020,27(1):10.
[12] ZHANG J,TANG P,ZOU L,et al.Discovery of novel dual-target inhibitor of bromodomain-containing protein 4/casein kinase 2 inducing apoptosis and autophagy-associated cell death for triple-negative breast cancer therapy［J］.J Med Chem,2021,64(24):18025-18053.
[13] LUM LG,RATHORE R,CUMMINGS F,et al.Phase I/II study of treatment of stage IV breast cancer with OKT3 x trastuzumab-armed activated T cells［J］.Clin Breast Cancer,2003,4(3):212-217.
[14] HAN KT,KIM S.Lipid-lowering drug adherence and combination therapy effects on gastrointestinal cancer in patients with dyslipidemia without diabetes:a retrospective cohort study in South Korea［J］.BMC Cancer,2022,22(1):156.
[15] MADEJ-CZERWONKA B,KORGA-PLEWKO A.Metatypical basal cell carcinoma:from the primary tumour to a generalized metastatic process - description of diagnostics and combination therapy of an extremely rare skin cancer［J］.Ann Agric Environ Med,2022,29(1):152-156.
[16] WANG J,SUN J,LIU LN,et al.Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy［J］.Nat Med,2019,25(4):656-666.
[17] BARENWALDT A,LAUBLI H.The sialoglycan-Siglec glyco-immune checkpoint - a target for improving innate and adaptive anti-cancer immunity［J］.Expert Opin Ther Targets,2019,23(10):839-853.
[18] HE F,WANG N,LI J,et al.High affinity monoclonal antibody targeting Siglec-15 for cancer immunotherapy［J］.J Clin Transl Res,2021,7(6):739-749.
[19] KAMAT NV,YU EY,LEE JK.BiTE-ing into prostate cancer with bispecific T-cell engagers［J］.Clin Cancer Res,2021,27(10):2675-2677.
[20] ZHENG M,YU L,HU J,et al.Efficacy of B7-H3-redirected BiTE and CAR-T immunotherapies against extranodal nasal natural killer/T cell lymphoma［J］.Transl Oncol,2020,13(5):100770.
[21] LASZLO GS,GUDGEON CJ,HARRINGTON KH,et al.Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody,AMG 330,against human AML［J］.Blood,2014,123(4):554-561.

Memo

Memo:
海南省重点研发计划项目（编号：ZDYF2018152）
Last Update: 1900-01-01