Growth factors that contribute to tumor angiogenesis, including Vascular Endothelial Growth Factor-A (VEGFA) and Placental Growth Factor 2 (PlGF2), are upregulated across many cancer types, yet there lacks an FDA-approved antibody (Ab) to mitigate their overexpression with sufficient cross-reactivity, specificity and affinity with minimal off-target effects. Though progress has been made to design Abs to block VEGFA interactions with its family of Vascular Endothelial Growth Factor Receptors (VEGFRs) and its co-receptor, neuropilin 1 (NRP1), the introduction of anti-VEGFA Abs can lead to therapeutic escape by expressing related PlGF2. However, sequence homology between growth factors can be leveraged to design cross-reactive antibodies to simultaneously target VEGFA and PlGF2 and their interactions with VEGFR1 and NRP1. This presents an opportunity to improve Ab properties in vivo and expand clinical translatability, which could best be addressed through an iterative approach integrating experimental assays and computational modeling. To this end, a recently determined suite of novel candidate Abs and demonstrated modest affinity and specificity/cross-reactivity for VEGFA, PlGF2. Herein, we employ physics-based computational tools to elucidate the residue-level interactions between the newly derived antibodies, relevant growth factors, receptors, and coreceptors. Characterization of this antibody suite through in silico approaches advances efforts to optimize immunoengineering design pipelines for robust and translatable VEGFA and PlGF2-mediated cancer therapeutics.
