Macrophages and Fc-receptor interactions contribute to the antitumour activities of the anti-CD40 antibody SGN-40

SGN-40 is a therapeutic antibody targeting CD40, which induces potent anti-lymphoma activities via direct apoptotic signalling cells and by cell-mediated cytotoxicity. Here we show antibody-dependent cellular phagocytosis (ADCP) by macrophages to contribute significantly to the therapeutic activities and that the antitumour effects of SGN-40 depend on Fc interactions

Erratum to: Analysis of in vitro ADCC and clinical response to trastuzumab: possible relevance of Fc\u3b3RIIIA/Fc\u3b3RIIA gene polymorphisms and HER-2 expression levels on breast cancer cell lines

BACKGROUND: Trastuzumab is a humanized monoclonal antibody (mAb) currently used for the treatment of breast cancer (BC) patients with HER-2 overexpressing tumor subtype. Previous data reported the involvement of FcγRIIIA/IIA gene polymorphisms and/or antibody-dependent cellular cytotoxicity (ADCC) in the therapeutic efficacy of trastuzumab, although results on these issues are still controversial. This study was aimed to evaluate in vitro the functional relationships among FcγRIIIA/IIA polymorphisms, ADCC intensity and HER-2 expression on tumor target cells and to correlate them with response to trastuzumab. PATIENTS AND METHODS: Twenty-five patients with HER-2 overexpressing BC, receiving trastuzumab in a neoadjuvant (NEO) or metastatic (MTS) setting, were genotyped for the FcγRIIIA 158V>F and FcγRIIA 131H>R polymorphisms by a newly developed pyrosequencing assay and by multiplex Tetra-primer-ARMS PCR, respectively. Trastuzumab-mediated ADCC of patients’ peripheral blood mononuclear cells (PBMCs) was evaluated prior to therapy and measured by (51)Chromium release using as targets three human BC cell lines showing different levels of reactivity with trastuzumab. RESULTS: We found that the FcγRIIIA 158F and/or the FcγRIIA 131R variants, commonly reported as unfavorable in BC, may actually behave as ADCC favorable genotypes, in both the NEO (P ranging from 0.009 to 0.039 and from 0.007 to 0.047, respectively) and MTS (P ranging from 0.009 to 0.032 and P = 0.034, respectively) patients. The ADCC intensity was affected by different levels of trastuzumab reactivity with BC target cells. In this context, the MCF-7 cell line, showing the lowest reactivity with trastuzumab, resulted the most suitable cell line for evaluating ADCC and response to trastuzumab. Indeed, we found a statistically significant correlation between an increased frequency of patients showing ADCC of MCF-7 and complete response to trastuzumab in the NEO setting (P = 0.006). CONCLUSIONS: Although this study was performed in a limited number of patients, it would indicate a correlation of FcγR gene polymorphisms to the ADCC extent in combination with the HER-2 expression levels on tumor target cells in BC patients. However, to confirm our findings further experimental evidences obtained from a larger cohort of BC patients are mandatory. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12967-015-0680-0) contains supplementary material, which is available to authorized users

More insight into the fate of biomedical meeting abstracts: a systematic review

BACKGROUND: It has been estimated that about 45% of abstracts that are accepted for presentation at biomedical meetings will subsequently be published in full. The acceptance of abstracts at meetings and their fate after initial rejection are less well understood. We set out to estimate the proportion of abstracts submitted to meetings that are eventually published as full reports, and to explore factors that are associated with meeting acceptance and successful publication. METHODS: Studies analysing acceptance of abstracts at biomedical meetings or their subsequent full publication were searched in MEDLINE, OLDMEDLINE, EMBASE, Cochrane Library, CINAHL, BIOSIS, Science Citation Index Expanded, and by hand searching of bibliographies and proceedings. We estimated rates of abstract acceptance and of subsequent full publication, and identified abstract and meeting characteristics associated with acceptance and publication, using logistic regression analysis, survival-type analysis, and meta-analysis. RESULTS: Analysed meetings were held between 1957 and 1999. Of 14945 abstracts that were submitted to 43 meetings, 46% were accepted. The rate of full publication was studied with 19123 abstracts that were presented at 234 meetings. Using survival-type analysis, we estimated that 27% were published after two, 41% after four, and 44% after six years. Of 2412 abstracts that were rejected at 24 meetings, 27% were published despite rejection. Factors associated with both abstract acceptance and subsequent publication were basic science and positive study outcome. Large meetings and those held outside the US were more likely to accept abstracts. Abstracts were more likely to be published subsequently if presented either orally, at small meetings, or at a US meeting. Abstract acceptance itself was strongly associated with full publication. CONCLUSIONS: About one third of abstracts submitted to biomedical meetings were published as full reports. Acceptance at meetings and publication were associated with specific characteristics of abstracts and meetings

Clearance of red cells by monoclonal IgG3 anti-D in vivo is affected by the VF polymorphism of Fc gamma RIIIa (CD16)

Human red cells (RBC) coated with IgG anti-D are cleared from the circulation to the spleen by macrophages which express IgG receptors (Fcgamma R). Polymorphisms of Fcgamma RIIa and Fcgamma RIIIa affect IgG binding in vitro , and may alter the efficiency of clearance of immune complexes in vivo. In a RBC clearance study, 22 Rh D-negative subjects were given 100-400 mug human monoclonal or polyclonal IgG anti-D i.m. followed 48 h later by Cr-51-labelled D+ RBC. The half lives of the infused D+ RBC were determined, together with the coating levels of anti-D on the D+ RBC. Fcgamma RIIA and FcgammaRIIIA genotyping was performed. Large ranges of phagocytosis and extracellular lysis of RBC in vitro, and of half lives of RBC in vivo, were observed. Clearance of RBC coated with monoclonal IgG3 anti-D (BRAD-3) was more rapid in five subjects homozygous for Fcgamma RIIIa-F/F158 than in three subjects expressing the Fcgamma RIIIa-V158 allele (P = 0.024). This effect was not observed, however, for those individuals given polyclonal anti-D. There was also no significant difference in the efficiency of RBC destruction in vitro or of RBC clearance in vivo between the subjects analysed for individual genotypes or alleles or combinations of alleles. In conclusion, the presence of the Fcgamma RIIIa-V158 allele compromised the efficiency of removal of RBC coated with IgG3 anti-D