Cancer Research

Targeted cancer therapy has become a new generation of cancer treatment, one which delivers drugs to specific carriers and interferes with the specific target molecules that play a critical role in tumor growth or progression (1).

For example, exosomes, small vesicles expressing specific surface markers (CD81, CD63, and CD9), play roles in cancer progression and tumorigenesis as a transporter of miRNA. As a delivery system, they can potentially be used as a specific carrier of immunotherapy/chemotherapy and cancer vaccines (2, 3). Activated T-cell surface receptors functioning as immune-checkpoints, such as programmed death 1 protein (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), both mediate immunosuppression by binding to PD-1 ligands (PD-L1 or PD-L2) and CTLA-4 ligands (CD80 or CD86) on antigen presentation cells, respectively. Inhibiting the interaction between PD-1/CTLA-4 and their ligands can lead to anti-tumor activity through T-cell activation (5, 6).

Chondrex, Inc. has developed a variety of reagents to investigate targeted cancer therapy. Our Exosome Detection ELISA kits quantify exosome levels in culture media, serum, and plasma. In addition, Chondrex, Inc. also provides monoclonal antibodies against common exosome markers and immune checkpoint ligands for immunostaining, ELISA, or flow cytometry.

Exosome ELISA Kits

	Product	Catalog #	Price (USD)
	Human CD63 Expressed Exosome Detection Assay Kit (BACK ORDERED UNTIL FURTHER NOTICE)	6037	389.00
	Human CD9 Expressed Exosome Detection Assay Kit	6036	389.00
	Human CD9 x CD63 Expressed Exosome Detection Assay Kit	6038	389.00

Exosome Marker Antibodies

	Product	Quantity	Catalog #	Price (USD)
	Mouse Anti-Human CD63 IgG Monoclonal Antibody, Clone 1B12E10	1 mg/ml x 0.1 ml	7119	246.00
	Mouse Anti-Human CD63 IgG Monoclonal Antibody, Clone 1B9C2	1 mg/ml x 0.1 ml	7118	246.00
	Mouse Anti-Human CD9 IgG Monoclonal Antibody, Clone 1H1H7	1 mg/ml x 0.1 ml	7114	246.00

Immune Checkpoint Antibodies

	Product	Quantity	Catalog #	Price (USD)
	Mouse Anti-Mouse CTLA4 IgG1 Monoclonal Antibody, Clone 3B8C7	1 mg/ml x 0.1 ml	7130	246.00
	Mouse Anti-Mouse CTLA4 IgG2a Monoclonal Antibody, Clone 4E12D1	1 mg/ml x 0.1 ml	7131	246.00
	Mouse Anti-Mouse PD-1 IgG Monoclonal Antibody, Clone 2H2H11	1 mg/ml x 0.1 ml	7123	246.00
	Mouse Anti-Mouse PD-L1 IgG Monoclonal Antibody, Clone 3A9F12	1 mg/ml x 0.1 ml	7122	246.00

Immune Checkpoint Antibodies for Melanoma Model

	Product	Quantity	Catalog #	Price (USD)
	Mouse Anti-Mouse CTLA4 IgG2a Monoclonal Antibody, Clone 2H9G9, 2 mg/ml x 5 ml	2 mg/ml x 5 ml	7133	540.00
	Mouse Anti-Mouse PD-L1 IgG2b Monoclonal Antibody, Clone 3H9G2, 2 mg/ml x 5 ml	2 mg/ml x 5 ml	7134	540.00

Background

Cancer can be considered as an inability of the host to eliminate transformed cells.  Surgery is the primary method of treatment for most isolated solid cancers and may work to prolong survival.  However, chemotherapy and radiation are generally still used to treat many types of cancers.  Recently, targeted therapy has emerged as a new generation of cancer drugs designed to interfere with specific target molecules (proteins) that contribute to tumor growth or progression. Furthermore, these new therapeutics and drug designs have been used to improve current drug therapies. (1).  

We introduce the following strategies for our targeted cancer therapies products.

1) Exosomes for a drug delivery system
Exosomes are small vesicles (30-100 nm) produced by most cell types. They carry a wide variety of cargo including nucleic acids (miRNA) and proteins, which stimulate receiving cells and produce a variety of downstream effects. Therefore, they play important roles in intercellular communication, including immune-modulation and coordination of cellular motility which have important implications for a wide variety of diseases.  Also, cancer patients have unusually high levels of exosomes in bodily fluids, suggesting that exosomes play a role in cancer progression and tumorigenesis. 

For example, cancer stem cells (CSCs) arise from epithelial to mesenchymal transition (EMT) and may contribute to recurrence of malignancy. The exosomes secreted from breast CSCs and chemoresistant cells contain miRNA-155. When the recipient cells receive exosomes containing miRNA-155, the cells obtain chemoresistance (2). Some exosomes express specific molecules on their membrane surfaces that can modulate immune reaction.  Exosomes isolated from mature dendritic cells (DCs) that express ICAM-1 on their surface can induce T-cell proliferation directly. Interestingly, exosomes from mature DCs are also able to confer antigen presentation ability to B-cells, thus activating naοve T-cells (3).  DCs that express IL-4 or Fas ligands were reported to reduce the development of murine arthritis (4-5).  Interestingly, exosomes derived from immature DCs treated with immunomodulatory cytokines IL-10 and IL-4 suppress the onset and severity of murine collagen-induced arthritis (6-7).  

Unlike synthetic nanoparticles, exosomes are biocompatible and biodegradable, and thus have low toxicity and immunogenicity, making them ideal for drug loading and delivering chemotherapy and cancer vaccines (8-9).  Therefore, it is critical that reliable methods for isolating intact exosomes are available as well as methods for evaluating exosome properties such as size and surface markers.

2) Immune-checkpoint therapy
Tumors develop multiple resistance mechanisms, including local immune suppression (10). Programmed death 1 protein (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are key immune checkpoint receptors expressed by activated T-cells, and they mediate immunosuppression by binding to PD-1 ligands (PD-L1 and PD-L2) and CTLA-4 ligands (B7-1 and B7-2), respectively, which are expressed by tumor cells. Inhibition of the interactions between PD-1/CTLA-4 and their ligands can enhance T-cell responses, leading to anti-tumor activity (11, 12).
Chondrex, Inc. not only provides reagents for cancer research, but also reagents to induce autoimmune disease models such as arthritis, ELISA kits to assay cytokines and chemokines, and antibodies to detect cancer markers.

References

1. C. Sawyers. Targeted cancer therapy. Nature 10, 1–4 (2004).
2. J. Santos, N. Lima, L. Sarian, A. Matheu, M. Ribeirio, et al. Exoxome-mediated breast cancer chemosresistance via miR-155 transfer. Sci Rep. 8, 829 (2018).
3. E. Segura, C. Nicco, B. Lombard, P. Vιron, G. Raposo, et al., ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood 106, 216-23 (2005).
4. S. Kim, S. Kim, C. Evans, S. Ghivizzani, T. Oligino, P. Robbins, et al., Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4. J Immunol 166, 3499-505 (2001).
5. S. Kim, N. Bianco, R. Menon, E. Lechman, W. Shufesky, et al., Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol Ther 13, 289-300 (2006).
6. S. Kim, E. Lechman, N. Bianco, R. Menon, A. Keravala, et al., Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. J Immunol 174, 6440-8 (2005).
7. N. Bianco, S. Kim, A. Morelli, P. Robbins, Modulation of the immune response using dendritic cell-derived exosomes. Methods Mol Biol 380, 443-55 (2007).
8. J. Wang, Y. Zheng, M. Zhao, Exosome-Based Cancer Therapy: Implication for Targeting Cancer Stem Cells. Front. Pharmacol. 7, 4360–11 (2017).
9. Y. Fujita, Y. Yoshioka, T. Ochiya, Extracellular vesicle transfer of cancer pathogenic components. Cancer Sci. 107, 385–390 (2016).
10. C. Wang et al., In Vitro Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and In Vivo Toxicology in Non-Human Primates. Cancer Immunology Research. 2, 846–856 (2014).
11. S. L. Topalian et al., Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. N Engl J Med. 366, 2443–2454 (2012).
12. E. I. Buchbinder, A. Desai, CTLA-4 and PD-1 Pathways. American Journal of Clinical Oncology. 39, 98–106 (2016).