Immunological Responses against HER2-targeted Idarubicin-ZHER2 Conjugate in BALB/c Mice
Targeting of cancerous cells with a high level of human epidermal growth factor receptor 2 (HER2) expressions by drug immunoconjugates is a new approach for specific delivery of chemotherapeutic agents. Our previous work indicated that idarubicin-ZHER2 affibody conjugate has a great potential for the treatment of HER2-overexpressing malignant cell lines but possible induced immune response against constructed conjugate was not addressed. In the current study, the possibility of induction of humoral and cellular immune responses against idarubicin-ZHER2 affibody conjugate in BALB/c mice was investigated. For assessment of the induced immune response, prepared and qualified idarubicin-ZHER2 affibody conjugate was administrated intravenously to BALB/c mice and the induced cellular immune response was evaluated by measuring secretion levels of interferon gamma (IFN-γ) and interleukin 10 (IL-10) cytokines by the splenocytes. Humoral response of treated mice was also assessed by measuring total immunoglobulin G (IgG) titer in mice sera. The obtained results showed that idarubicin-ZHER2 affibody conjugate at any examined concentrations could not induce secretion of IFN-γ as a pro-inflammatory cytokine. A mild increase in the level of regulatory IL-10 cytokine was seen in the treated mice although no dose dependency in the level of IL-10 production was observed. Furthermore, results showed that idarubicin-ZHER2 conjugate could not induce IgG production in the treated mice. Based on these findings, the idarubicin-ZHER2 conjugate can be considered as a candidate for the development of new therapeutics against HER2-overexpressing cancers although further in vivo studies are needed.
- Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Reviews Cancer 2005; 5: 341-354.
- Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. The EMBO journal 2000; 19: 3159-3167.
- Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA. (2003). EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Molecular cell 2003; 11:507-517.
- Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 2003; 421(6924):756-60.
- Vermeij J, Teugels E, Bourgain C, Xiangming J, Ghislain V, Neyns B, et al. Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers. BMC cancer 2008; 8(1):3.
- Jaehne J, Urmacher C, Thaler H, Friedlander-Klar H, Cordon-Cardo C, Meyer H. Expression ofHer2/neu oncogene product p185 in correlation to clinicopathological and prognostic factors of gastric carcinoma. Journal of cancer research and clinical oncology 1992; 118(6):474-9.
- Cornolti G, Ungari M, Morassi ML, Facchetti F, Rossi E, Lombardi D, et al. Amplification and overexpression of HER2/neu gene and HER2/neu protein in salivary duct carcinoma of the parotid gland. Archives of Otolaryngology–Head & Neck Surgery 2007; 133(10):1031-6.
- Slamon D. Human breast cancer: correlation of relapse and. Science 1987; 3798106(177):235.
- Chen JS, Lan K, Hung MC. Strategies to target HER2/neu overexpression for cancer therapy. Drug resistance updates 2003; 6(3):129-36.
- Olayioye MA. Intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Research 2001; 3(6):385.
- Neve R, Lane H, Hynes N. The role of overexpressed HER2 in transformation. Annals of oncology 2001; 12(suppl 1):S9-S13.
- Ménard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003; 22(42):6570-8.
- Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New England Journal of Medicine 2001; 344(11):783-92.
- Guan Z, Xu B, DeSilvio ML, Shen Z, Arpornwirat W, Tong Z, et al. Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2–overexpressing metastatic breast cancer. Journal of Clinical Oncology 2013; 31(16):1947-53.
- Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. New England Journal of Medicine 2012; 367(19):1783-91.
- Lambert JM, Chari RV. Ado-trastuzumab Emtansine (T-DM1): an antibody–drug conjugate (ADC) for HER2-positive breast cancer. ACS Publications; 2014.
- Uhlen M, Guss B, Nilsson B, Gatenbeck S, Philipson L, Lindberg M. Complete sequence of the staphylococcal gene encoding protein A. A gene evolved through multiple duplications. Journal of Biological Chemistry 1984; 259(3):1695-702.
- Tai W, Mahato R, Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. Journal of Controlled Release 2010; 146(3):264-75.
- Pu KY, Shi J, Cai L, Li K, Liu B. Affibody-attached hyperbranched conjugated polyelectrolyte for targeted fluorescence imaging of HER2-positive cancer cell. Biomacromolecules 2011; 12(8):2966-74.
- Puri A, Kramer-Marek G, Campbell-Massa R, Yavlovich A, Tele SC, Lee SB, et al. HER2-specific affibody-conjugated thermosensitive liposomes (Affisomes) for improved delivery of anticancer agents. Journal of liposome research 2008; 18(4):293-307.
- Zhang Y, Jiang S, Zhang D, Bai X, Hecht SM, Chen S. DNA–affibody nanoparticles for inhibiting breast cancer cells overexpressing HER2. Chemical Communications 2017; 53(3):573-6.
- Ghanemi M, Pourshohod A, Ghaffari M, Kheirollah A, Amin M, Zeinali M, et al. Specific targeting of HER2-positive head and neck squamous cell carcinoma line HN5 by Idarubicin-ZHER2 affibody conjugate. Current cancer drug targets 2017.
- Wahlberg E, Lendel C, Helgstrand M, Allard P, Dincbas-Renqvist V, Hedqvist A, et al. An affibody in complex with a target protein: structure and coupled folding. Proceedings of the National Academy of Sciences 2003; 100(6):3185-90.
- Inoue H, Nojima H, Okayama H. High efficiency transformation of Escherichia coli with plasmids. Gene 1990; 96(1):23-8.
- Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical biochemistry 1976; 72(1-2):248-54.
- Daifalla NS, Bayih AG, Gedamu L. Differential Immune Response against Recombinant Leishmania donovani Peroxidoxin 1 and Peroxidoxin 2 Proteins in BALB/c Mice. Journal of immunology research 2015; 2015(1.
- Orlova A, Magnusson M, Eriksson TL, Nilsson M, Larsson B, Höidén-Guthenberg I, et al. Tumor imaging using a picomolar affinity HER2 binding affibody molecule. Cancer research 2006; 66(8):4339-48.
- Eigenbrot C, Ultsch M, Dubnovitsky A, Abrahmsén L, Härd T. Structural basis for high-affinity HER2 receptor binding by an engineered protein. Proceedings of the National Academy of Sciences 2010; 107(34):15039-44.
- Carrasco-Triguero M. Insights on the immunogenicity of antibody–drug conjugates. Bioanalysis 2015; 7(13):1565-8.
- Nahta R, Yu D, Hung M-C, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nature clinical practice Oncology 2006; 3(5):269-80.
- Phillips GDL, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody–cytotoxic drug conjugate. Cancer research 2008; 68(22):9280-90.