Immunotoxins (ITXs) are chimeric molecules that combine the specificity of a targeting domain, usually derived from an antibody, and the cytotoxic potency of a toxin, leading to the selective death of tumor cells. However, several issues must be addressed and optimized in order to use ITXs as therapeutic tools, such as the selection of a suitable tumor-associated antigen (TAA), high tumor penetration and retention, low kidney elimination, or low immunogenicity of foreign proteins. To this end, we produced and characterized several ITX designs, using a nanobody against EGFR (V_HH 7D12) as the targeting domain. First, we generated a nanoITX, combining V_HH 7D12 and the fungal ribotoxin α-sarcin (αS) as the toxic moiety (V_HHEGFRαS). Then, we incorporated a trimerization domain (TIE^XVIII) into the construct, obtaining a trimeric nanoITX (TriV_HHEGFRαS). Finally, we designed and characterized a bispecific ITX, combining the V_HH 7D12 and the scFv against GPA33 as targeting domains, and a deimmunized (DI) variant of α-sarcin (BsITXαSDI). The results confirm the therapeutic potential of α-sarcin-based nanoITXs. The incorporation of nanobodies as target domains improves their therapeutic use due to their lower molecular size and binding features. The enhanced avidity and toxic load in the trimeric nanoITX and the combination of two different target domains in the bispecific nanoITX allow for increased antitumor effectiveness.

During pregnancy, the maternal body adapts in several ways to create an optimal environment for embryonic growth. These changes include endocrine and metabolic shifts that can lead to insulin resistance and gestational diabetes mellitus (GDM), impacting both the mother and fetus in the short and long term. Fetal macrosomia, a condition where the fetus is significantly larger than average, is a primary concern associated with GDM. Although the underlying mechanism remains unclear, a pregnancy-induced proinflammatory state, combined with altered glucose homeostasis, plays a critical role. Several cytokines and hormones, such as interleukin 6 (IL-6), insulin growth factor 1 (IGF-1), prolactin (PRL), or progesterone, are essential for fetal growth, the control of the inflammatory response, and the regulation of lipid and carbohydrate metabolism to meet energy demands during pregnancy. However, although the role of these cytokines in metabolism and body growth during adulthood has been extensively studied, their implication in the pathophysiology of GDM and macrosomia is not well understood. Here, we review this pathophysiology and pose the hypothesis that an aberrant response to cytokine receptor activation, particularly involving the suppressor of cytokine signaling 2 (SOCS2), contributes to GDM and fetal macrosomia. This novel perspective suggests an unexplored mechanism by which SOCS2 dysregulation could impact pregnancy outcomes.