+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Efficacy of anti-RON antibody Zt/g4-drug maytansinoid conjugation (Anti-RON ADC) as a novel therapeutics for targeted colorectal cancer therapy

, : Efficacy of anti-RON antibody Zt/g4-drug maytansinoid conjugation (Anti-RON ADC) as a novel therapeutics for targeted colorectal cancer therapy. Clinical Cancer Research 20(23): 6045-6058

The receptor tyrosine kinase RON is critical in epithelial tumorigenesis and a drug target for cancer therapy. Here, we report the development and therapeutic efficacy of a novel anti-RON antibody Zt/g4-maytansinoid (DM1) conjugates for targeted colorectal cancer (CRC) therapy. Zt/g4 (IgG1a/κ) was conjugated to DM1 via thioether linkage to form Zt/g4-DM1 with a drug-antibody ratio of 4:1. CRC cell lines expressing different levels of RON were tested in vitro to determine Zt/g4-DM1-induced RON endocytosis, cell-cycle arrest, and cytotoxicity. Efficacy of Zt/g4-DM1 in vivo was evaluated in mouse xenograft CRC tumor model. Zt/g4-DM1 rapidly induced RON endocytosis, arrested cell cycle at G2-M phase, reduced cell viability, and caused massive cell death within 72 hours. In mouse xenograft CRC models, Zt/g4-DM1 at a single dose of 20 mg/kg body weight effectively delayed CRC cell-mediated tumor growth up to 20 days. In a multiple dose-ranging study with a five injection regimen, Zt/g4-DM1 inhibited more than 90% tumor growth at doses of 7, 10, and 15 mg/kg body weight. The minimal dose achieving 50% of tumor inhibition was approximately 5.0 mg/kg. The prepared Zt/g4-DM1 is stable at 37°C for up to 30 days. At 60 mg/kg, Zt/g4-DM1 had a moderate toxicity in vivo with an average of 12% reduction in mouse body weight. Zt/g4-DM1 is highly effective in targeted inhibition of CRC cell-derived tumor growth in mouse xenograft models. This work provides the basis for development of humanized Zt/g4-DM1 for RON-targeted CRC therapy in the future.


PMID: 25294907

DOI: 10.1158/1078-0432.CCR-14-0898

Other references

Lugeder, A.; Häring, E.; Müller, A.; Droste, P.; Dorste, P.; Zeichen, J., 2014: Total hip arthroplasty with the cementless spiron femoral neck prosthesis. Cementless total hip arthroplasty with preservation of femoral neck and natural load transmission. Restoration of joint function and alleviation of pain. Osteoarthritis of the hip or femoral head necrosis in younger patients. Patients biologically...

Weber, D.; Weber, M., 2016: Corrective Osteotomies for Malunited Malleolar Fractures. Ankle fractures are common and may be treated nonoperatively or by reduction and internal fixation. Both treatments may lead to nonanatomic healing, called malunions. Malunions lead to joint instability and pathologic load transfer. Arthritic join...

Bhatt P.N.; Bhatt D.P., 1984: Regulation of sterol biosynthesis in solanum species. Regulation of sterol synthesis was studied in Solanum spp. A significant negative correlation was found between sterol content and rate of sterol synthesis from (1-14C) acetate in plant organs of S. nigrum and cell cultures of S. dulcamara. Exogen...

Matos, A.; Garland, J.L., 2005: Effects of community versus single strain inoculants on the biological control of Salmonella and microbial community dynamics in alfalfa sprouts. Potential biological control inoculants, Pseudomonas fluorescens 2-79 and microbial communities derived from market sprouts or laboratory-grown lucerne sprouts, were introduced into lucerne seeds with and without a Salmonella inoculum. We examined...

Elias, J., 1992: The multicoloured species Pseudocrenilabrus multicolor.. Akvarium Terarium 35.3: 2-4

Anonymous, 1995: Health service staff support French public sector strike. NlmCategory="UNASSIGNED">French nurses supported the public sector strike which brought the country to a standstill last week, but few actually took action.

Kataoka, M.; Shimizu, Y.; Margenthaler, J.A.; Landeros, K.; Otomo, N.; Flye, M.W.yne, 2002: Transfer of infectious cardiac allograft tolerance induced by donor-specific transfusion. Background. "Infectious tolerance" has been defined as the tolerance induced in a new recipient by the adoptive transfer of cells from a recipient accepting an allograft after anti-CD4 and anti-CD8 monoclonal antibody treatment. A clear...

Pires, A.L. de F., 1990: Liming for forages on acid soils of northern Portugal. Two greenhouse experiments and a 2-year field study were conducted to evaluate the effect of calcitic or dolomitic lime applications on yield and mineral composition of forage species that are commonly used, or have the potential of being grown, i...

Cowen James P.; Bertram Miriam A.; Baker Edward T.; Feely Richard A.; Massoth Gary J.; Summit Melanie, 1998: Geomicrobial transformation of manganese in Gorda River event plumes. Deep Sea ResearchII: Topical Studies in Oceanography. 45; 12, Pages 2713-2737. 1998.

Langlotz, K., 1932: Experiments on the Diagnosis of Pregnancy in Cattle by the Demonstration of the Ovarian Hormone in the Urine. III. The author applied the technique of Kust in an investigation to determine whether the ovarian hormone is excreted in the urine of pregnant cows. He found that, using urine treated with ether, positive results could be obtained from the 23rd w...