Lai, Phei San and Usama, Syed Muhammad and Kiew, Lik Voon and Lee, Hong Boon and Chung, Lip Yong and Burgess, Kevin and Kue, Chin Siang (2022) Antibody-dependent cellular phagocytosis of tropomyosin receptor kinase C (TrkC) expressing cancer cells for targeted immunotherapy. Cancer Immunology Immunotherapy, 71 (9). pp. 2099-2108. ISSN 0340-7004, DOI https://doi.org/10.1007/s00262-022-03147-y.
Full text not available from this repository.Abstract
Conventional cancer therapies such as chemotherapy are non-selective and induce immune system anergy, which lead to serious side effects and tumor relapse. It is a challenge to prime the body's immune system in the cancer-bearing subject to produce cancer antigen-targeting antibodies, as most tumor-associated antigens are expressed abundantly in cancer cells and some of normal cells. This study illustrates how hapten-based pre-immunization (for anti-hapten antibodies production) combined with cancer receptor labeling with hapten antigen constructs can elicit antibody-dependent cellular phagocytosis (ADCP). Thus, the hapten antigen 2,4-dinitrophenol (DNP) was covalently combined with a cancer receptor-binding dipeptide (IYIY) to form a dipeptide-hapten construct (IYIY-DNP, MW = 1322.33) that targets the tropomyosin receptor kinase C (TrkC)-expressed on the surface of metastatic cancer cells. IYIY-DNP facilitated selective association of RAW264.7 macrophages to the TrkC expressing 4T1 cancer cells in vitro, forming cell aggregates in the presence of anti-DNP antibodies, suggesting initiation of anti-DNP antibody-dependent cancer cell recognition of macrophages by the IYIY-DNP. In in vivo, IYIY-DNP at 10 mg/kg suppressed growth of 4T1 tumors in DNP-immunized BALB/c mice by 45% (p < 0.05), when comparing the area under the tumor growth curve to that of the saline-treated DNP-immunized mice. Meanwhile, IYIY-DNP at 10 mg/kg had no effect on TrkC-negative 67NR tumor-bearing mice immunized with DNP. Tumor growth suppression activity of IYIY-DNP in DNP-immunized mice was associated with an increase in the anti-DNP IgG (7.3 x 10(6) +/- 1.6 U/mL) and IgM (0.9 x 10(6) +/- 0.07 U/mL) antibodies after five cycles of DNP treatment, demonstrated potential for hapten-based pre-immunization then treatment with IYIY-DNP to elicit ADCP for improved immunotherapy of TrkC expressing cancers.
| Item Type: | Article |
|---|---|
| Funders: | Ministry of Higher Education Malaysia Fundamental Research Grant Scheme (Grant No: FRGS/1/2020/SKK0/MSU/02/1), National Cancer Council Malaysia (MAKNA) Cancer Research Award (CRA) 2017, United States Department of Health & Human Services National Institutes of Health (NIH) - USA (Grant No: R01EY029645), Texas A&M University T3-Grants Program (Grant No: 246292-00000) |
| Uncontrolled Keywords: | Dinitrophenol; Immunotherapy; Antibody-dependent cellular phagocytosis; TrkC; Ligand-hapten conjugate; Active targeting |
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Faculty of Medicine Faculty of Pharmacy > Department of Pharmaceutical Chemistry |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 25 Oct 2023 02:36 |
| Last Modified: | 25 Oct 2023 02:36 |
| URI: | http://eprints.um.edu.my/id/eprint/41765 |
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