Bispecific monoclonal antibodies can be used to redirect peripheral blood lymphocytes against tumor cells. In the present study, a murine bispecific monoclonal antibody was developed using somatic ...hybrydization. The antibody has two different binding arms: one arm directed against human CD3 receptor expressed on T-lymphocytes and the other against tumor associated glycoprotein TAG-72, expressed on human carcinomas, such as colon, breast, and pancreas. Partially purified antibody was capable of inducing human T-cell proliferation and preventing growth of colon cancer cell line in nu/nu mice in a tumor neutralization assay.
An experimental model of hepatic metastases in C57BL/6 mice was used to compare the antitumor effects of lymphokine-activated killer (LAK) cells, anti-CD3-activated T-cells (ATC), and anti-CD3 alone. ...Liver metastases were produced by in vivo passage of MCA-38-LD adenocarcinoma via the ileocolic vein. LAK cells and ATC were generated by 3-day in vitro incubation of spleen cells in interleukin 2 and anti-CD3, respectively. Percentage of tumor volume in livers was determined with a morphometric technique. With less than therapeutic LAK cell doses (0.5-1.0 x 10(7) cells), no effect was seen in mean (+SE, -SE) percentage of tumor volume of control 23.3 (29.3, 18.5) compared to LAK cell-treated 21.6 (29.3, 15.9) animals. The same number of ATC significantly reduced the mean percentage of tumor volume 2.7 (4.7, 1.4) (P less than 0.005). High dose interleukin 2 also significantly decreased tumor volume. More strikingly, a single dose of anti-CD3 alone had a beneficial effect on mean percentage of tumor volume when given i.p. 1.0 (1.9, 0.4) or i.v. 1.2 (1.7, 0.7) (P less than 0.0003). A total of 33% of anti-CD3-treated mice had no detectable liver metastases. In 51Cr release assays, the cytotoxicity of ATC was shown to be partially mediated by nylon wool-adherent accessory cells. The effectiveness of anti-CD3 in this immunotherapy model suggests that a similar approach may be taken to immunotherapy of human malignancies, without the requirements for in vitro-generated killer cells or exogenously administered interleukin 2.
Sixteen patients with colorectal cancer were administered 37-74 MBq (1 mg) of radioiodinated B72.3 monoclonal antibody. Pharmacokinetic analysis was carried out on plasma and urine samples. ...Elimination from the plasma was biexponential with a mean T1/2 alpha of 3.7 h and T1/2 beta of 62.4 h. The plasma clearance was fit to a two-compartmental model. This was combined with a previously reported model for radioiodine to construct a composite model. There was a good correlation (r = 0.952) between the model-predicted and observed excretion of radioiodine suggesting that the composite model is compatible with the pharmacokinetics of the radiolabelled antibody.
The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative ...trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (Po3.2 Â 10 À 13 ; FDRo5%). These trans-meQTLs include 1,657 SNP–CpG pairs from different chromosomes and 262 pairs from the same chromosome that are 41 Mb apart. Over 90% of these pairs are replicated (FDRo5%) in at least one of two independent data sets. Genomic loci harbouring trans-meQTLs are significantly enriched (Po0.001) for long non-coding transcripts (2.2-fold), known epigenetic regulators (2.3-fold), piwi-interacting RNA clusters (3.6-fold) and curated transcription factors (4.1-fold), including zinc-finger proteins (8.75-fold). Long-range epigenetic networks uncovered by this approach may be relevant to normal and disease states.
The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative ...trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (Po3.2 Â 10 À 13 ; FDRo5%). These trans-meQTLs include 1,657 SNP–CpG pairs from different chromosomes and 262 pairs from the same chromosome that are 41 Mb apart. Over 90% of these pairs are replicated (FDRo5%) in at least one of two independent data sets. Genomic loci harbouring trans-meQTLs are significantly enriched (Po0.001) for long non-coding transcripts (2.2-fold), known epigenetic regulators (2.3-fold), piwi-interacting RNA clusters (3.6-fold) and curated transcription factors (4.1-fold), including zinc-finger proteins (8.75-fold). Long-range epigenetic networks uncovered by this approach may be relevant to normal and disease states.
