Sex differences in angiogenesis inhibition by human IgG1 antibodies

Abstract

Purpose : Human IgG1 antibodies, which are highly abundant in plasma and a prevalent drug class (including bevacizumab), possess intrinsic antigen-independent angiogenesis inhibitory activity. We sought to determine the extent to which this activity differs by sex, and the molecular mechanisms underlying these differences.

Methods : Purified human IgG1 or control IgG2 were obtained from plasma of human myeloma patients. The ability of human IgG1 to suppress VEGF-dependent chemotaxis was modeled in primary single-donor human and mouse male and female macrophages. Angiogenesis inhibition was measured in mouse laser-induced choroidal neovascularization (CNV). The four core genotypes (FCG) mouse model was used to compare the contributions of sex chromosome complement and gonadal secretions, and the XY* mouse model of Turner Syndrome was used to further investigate the role of sex chromosomes. Sex chromosome-wide transcriptomics and siRNA screening were performed in human and mouse macrophages.

Results : IgG1-mediated inhibition of chemotaxis and angiogenesis was robust in male cells and mice, occured independently of antigen binding, and was abrogated in cells lacking the IgG1 receptor FcγR1. In each of the models tested (human and mouse cell models and mouse laser CNV), IgG1-mediated chemotaxis and angiogenesis inhibition was significantly greater in males than in females. The dimorphism was so great that in some cases, the data segregated by sex without overlap. The FCG mouse model indicated a role for sex chromosome complement in the dimorphic phenotype. Turner Syndrome mice revealed a potential role for the Y chromosome in this phenotype. Chromosome-wide transcriptomic and gene silencing screening identified candidate genes encoded on sex chromosomes as responsible for IgG1-mediated angiogenesis inhibition.

Conclusions : These findings identify sex as a key contributor to IgG1-mediated angiogenesis inhibition, implicate sex chromosome encoded genes in pathological blood vessel regulation, and highlight the importance of analyzing both sexes. Insights gleaned from these studies may lead to a better fundamental understanding of how pathological angiogenesis in males and females differs, and ultimately, how treatments can be personalized to improve outcomes for angiogenesis-related disorders.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.