14F7 murine monoclonal antibody (MAb) is an IgG1 immunoglobulin that is generated by immunizing Balb/c mice with GM3(NeuGc) ganglioside hydrophobically conjugated with human very-low-density lipoproteins and in the presence of Freund's adjuvants. 14F7 MAb binds specifically to GM3(NeuGc), whereas neither N-glycolyl or N-acetyl gangliosides, nor a sulfated glycolipid, are recognized as assessed by enzyme-linked immunosorbent assay or immunostaining on thin layer chromatograms. Immunohistochemical studies in fresh tumor tissues showed that 14F7 MAb strongly recognized in antigen expressed in human breast and melanoma tumors.
We conducted preregistered replications of 28 classic and contemporary published findings with protocols that were peer reviewed in advance to examine variation in effect magnitudes across sample and setting. Each protocol was administered to approximately half of 125 samples and 15,305 total participants from 36 countries and territories. Using conventional statistical significance (p < .05), fifteen (54%) of the replications provided evidence in the same direction and statistically significant as the original finding. With a strict significance criterion (p < .0001), fourteen (50%) provide such evidence reflecting the extremely high powered design. Seven (25%) of the replications had effect sizes larger than the original finding and 21 (75%) had effect sizes smaller than the original finding. The median comparable Cohen’s d effect sizes for original findings was 0.60 and for replications was 0.15. Sixteen replications (57%) had small effect sizes (< .20) and 9 (32%) were in the opposite direction from the original finding. Across settings, 11 (39%) showed significant heterogeneity using the Q statistic and most of those were among the findings eliciting the largest overall effect sizes; only one effect that was near zero in the aggregate showed significant heterogeneity. Only one effect showed a Tau > 0.20 indicating moderate heterogeneity. Nine others had a Tau near or slightly above 0.10 indicating slight heterogeneity. In moderation tests, very little heterogeneity was attributable to task order, administration in lab versus online, and exploratory WEIRD versus less WEIRD culture comparisons. Cumulatively, variability in observed effect sizes was more attributable to the effect being studied than the sample or setting in which it was studied.
Nimotuzumab is an EGFR-targeting antibody that has demonstrated encouraging clinical results in the absence of severe side-effects observed with other approved anti-EGFR antibodies. We investigated whether different clinical behavior of nimotuzumab is related to its bivalent/monovalent binding profile. Binding properties of nimotuzumab and cetuximab, the most development of anti-EGFR antibodies, were studied in vitro using chip surfaces and cells with varying EGFR expression levels. Experimental observations demonstrated that in contrast to cetuximab, the intrinsic properties of nimotuzumab required bivalent binding for stable attachment to the cellular surface, leading to nimotuzumab selectively binding to cells that express moderate to high EGFR expression levels. At these conditions, both antibodies bound bivalently, and accumulated to similar degrees. When EGFR density is low, nimotuzumab monovalent interaction was transient, whereas cetuximab continued to interact strongly with the receptors. We compared the in vitro anti-tumor efficacy of nimotuzumab and cetuximab. Cetuximab decreased the cell viability and induced apoptosis for all the tested cell lines, effects which did not depend on EGFR expression level. In contrast, nimotuzumab also provoked significant anti-cellular effects, but its anti-tumor capacity decreased together with EGFR expression level. Cetuximab Fab fragment was able to impact tumor cell survival, whereas nimotuzumab fragment totally lost this effect. Tumor-xenograft experiments using cells with a high EGFR expression revealed similar tumor growth inhibiting effects for both antibodies. This study suggests an explanation for nimotuzumab clinical profile, whereby anti-tumor activity is obtained in absence of severe toxicities due to its properties of bivalent binding to EGFR.
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