Beginning our occasional “quick hit” tour through recent poster and other data presentations of preclinical research is September news from Boston-based Zafgen Inc. regarding the sharing of ZGN-1061 results at the 53rd Annual Meeting of the European Association for the Study of Diabetes in Lisbon, Portugal. ZGN-1061, the company's second-generation MetAP2 inhibitor, is advancing toward a Phase 2 clinical trial in patients with type 2 diabetes. The company also shared some previously reported Phase 1 data.
As far as the preclinical study evaluating ZGN-1061 in a mouse model of obesity and insulin resistance, though, highlights include the finding that ZGN-1061 produced dose-dependent improvements in glucose tolerance and insulin levels in diet induced obese mice; that the compound produced a dose-dependent reduction in body weight that was primarily due to loss of fat mass; that improvements in glucose tolerance and insulin levels seen with ZGN-1061 also occurred with low dose levels which did not result in weight change and suggest these glucose homeostatic benefits can be dissociated, at least in part, from a weight loss effect or food intake effect; and indications of improvements in metabolic biomarkers, including non-esterified fatty acids, ketone bodies (β-hydroxybutyrate) and leptin, which were consistent with loss of fat mass as well as increased fat mobilization and oxidation.
Innate Pharma and cancer
Marseille, France-based Innate Pharma SA recently announced that new preclinical data for its first-in-class clinical stage antibodies IPH5401 and monalizumab were presented at the 3rd CRI-CIMT-EATI-AACR International Cancer Immunotherapy conference in September in Frankfurt, Germany.
Poster #B184 demonstrated that IPH5401 selectively inhibits the activation of neutrophils; moreover, the data show that the combined administration of anti-C5aR with anti-PD-1 reduced tumor growth. Taken together, these data suggest that C5aR blockade may result in a more permissive environment for immune-mediated tumor killing and treatment with checkpoint inhibitors.
Poster #A130 showed that blocking both NKG2A/HLA-E and PD-1/PD-L1 pathways enhance antitumor efficacy of CD8+ T cells. The data show that the deletion of either NKG2A (Qa-1b) or PD-L1 significantly delays tumor growth, suggesting that both receptors are involved in the immune-escape of tumors.
Idera and cancer
Also at the Frankfurt conference, Idera Pharmaceuticals Inc. (based in Massachusetts and Pennsylvania), a clinical-stage biopharmaceutical company developing Toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, reported new preclinical data from its ongoing intratumoral IMO-2125 development program.
In the poster presentation, it was demonstrated that intratumoral injections of IMO-2125 enhance anti-tumor responses in combination with CTLA4 blockade. Further this study demonstrated the combination of IMO-2125 and anti-CTLA4 achieves prolonged, durable antitumor effect.
In this study, mice whose tumors completely regressed survived more than one year after the combination treatment was administered. These animals maintained antitumor responses upon tumor re-challenge indicative of memory T cell induction by the combination of IMO-2125 and anti-CTLA4. Additionally, IMO-2125 delivered intratumorally has been shown to mediate tumor microenvironment changes including infiltration of T cells and immune checkpoint gene up-regulation.
argenx and dyslipidemia
From Netherlands/Belgium-based argenx, a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, came the late-August announcement of the publication in Nature Medicine of preclinical data on ARGX-116 inhibiting ApoC3, a metabolic target correlated with blood lipid levels. The data reportedly provide further rationale for the therapeutic potential of anti-ApoC3 SIMPLE AntibodyTM ARGX-116 for the treatment of dyslipidemia.
Data published by argenx collaborator Dr. Daniel Rader, from Staten Biotechnology and the University of Pennsylvania demonstrate that ARGX-116 accelerates ApoC3 clearance and lowers triglyceride-rich lipoproteins in mouse models, signifying a potential protective mechanism. These data could translate to a possible approach to reduce ApoC3 levels and circulating TRL burden in vivo, with therapeutic potential in triglyceride metabolism-related diseases, including dyslipidemia.