Antibody-drug conjugates (ADCs) have demonstrated clinical benefits that have led to the recent FDA approval of KADCYLA and ADCETRIS. Most ADCs that are currently in clinical use or development, including ADCETRIS, are produced by chemical conjugation of a toxin via either lysine or cysteine residues, inevitably leading to heterogeneous products with variable drug-to-antibody ratios (DARs). Here, we describe the in vitro and in vivo characterization of four novel ADCs that are based on the anti-CD30 antibody cAC10, which has the same polypeptide backbone as ADCETRIS, and compare the results with the latter. Bacterial transglutaminase (BTG) was exploited to site-specifically conjugate derivatives of monomethyl auristatin E (all comprising a cleavable linker) to the glutamine at positions 295 and 297 of cAC10, thereby yielding homogeneous ADCs with a DAR of 4. In vitro cell toxicity experiments using two different CD30-positive cell lines (Karpas 299 and Raji-CD30(+)) revealed comparable EC50 values for ADCETRIS (1.8 ± 0.4 and 3.6 ± 0.6 ng/mL, respectively) and the four cAC10-based ADCs (2.0 ± 0.4 to 4.9 ± 1.0 ng/mL). Quantitative time-dependent in vivo biodistribution studies (3-96 h p.i.) in normal and xenografted (Karpas 299 cells) SCID mice were performed with a selected (125)I-radioiodinated cAC10 ADC and compared with that of (125)I-ADCETRIS. The chemo-enzymatically conjugated, radioiodinated ADC showed higher tumor uptake (17.84 ± 2.2% ID/g 24 h p.i.) than (125)I-ADCETRIS (10.5 ± 1.8% ID/g 24 h p.i.). Moreover, (125)I-ADCETRIS exhibited higher nontargeted liver and spleen uptake. In line with these results, the maximum tolerated dose of the BTG-coupled ADC (>60 mg/kg) was significantly higher than that of ADCETRIS (18 mg/kg) in rats. These results suggest that homogeneous ADCs display improved pharmacokinetics and better therapeutic indexes compared to those of chemically modified ADCs with variable DARs.
Purpose The purpose of this study was to determine therapeutic effects and systemic toxicity of 212Pb-Trastuzumab in an orthotopic model of human prostate cancer cells in nude mice. Experimental Design TCMC-Trastuzumab was radiolabeled with 212Pb. The activity and integrity of 212Pb-Trastuzumab was confirmed by a competitive binding assay and SDS-PAGE analysis. Therapeutic effects were determined in an orthotopic model of human prostate cancer in nude mice. Body weight, blood cell counts, serum alanine transaminase (ALT), blood urea nitrogen (BUN), and tissue histology were examined to evaluate systemic toxicity of 212Pb-Trastuzumab therapy. Results The 212Pb-Trastuzumab generated from the procedure was intact and had high binding affinity with a dissociation constant (Kd) of 3.9 ± 0.99 nM. PC-3MM2 cells, which expressed relatively a lower level of Her2 both in culture and in tumors, were used in the study. A single injection of 212Pb-Trastuzumab reduced tumor growth by 60-80%, reduced aortic lymph node metastasis, and prolonged the survival of tumor-bearing mice. Treatment with 212Pb-Trastuzumab did not cause significant changes in body weight, serum SGPT and BUN, hematological profiles, and histological morphology of several major organs of tumor-bearing mice. Conclusion The data presented in this report demonstrated that the 212Pb-Trastuzumab therapy did not cause significant systemic toxicity and was very effective in retarding tumor growth and prolonging survival of mice bearing tumors that express very low levels of Her2. These findings suggest that 212Pb-Trastuzumab, used alone or in combination with other means, could be an effective modality for management of advanced human prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5713. doi:1538-7445.AM2012-5713
Gastrointestinal irritation is a common entity in trace mineral toxicosis. To determine the extent of trace mineral involvement in west-central Nebraska beef calves, trace elements analyses were performed on 144 livers from perinatal calves submitted to the Veterinary Science Laboratory, North Platte, Nebraska during 1983 and 1984. All calves originated from herds in west-central Nebraska and ranged in age from eight months of gestation up to six-week-old neonates. Perinates were subjected to complete gross and microscopic, bacteriologic, virologic and toxicologic examinations. The purpose of this preliminary study was to determine if trace mineral problems existed in west-central Nebraska, and if any relationship existed with potential disease syndromes. No single element appears responsible for neonatal calf diarrhea, but the variety of fluctuations indicate that trace elements play a role in many enteric syndromes. Supplementation of necessary elements in a proper protein and energy diet has improved production and lessened disease effects by reduced morbidity and mortality. Liver concentrations indicated above normal iron content as the most common trace mineral finding in calves with diarrhea. Hematology values were within normal ranges except for hemoglobin (Hgb) and hematocrit (Hct), which were above normal in both groups of CU cows and non CU cows. Other problems attributed to trace minerals include sudden death in calves, white muscle disease, poor nursing and unthriftiness in calves, retained placentas, infertility, achromotrichia and downer cows.
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