Fcγ-Receptor-Independent Controlled Activation of CD40 Canonical Signaling by Novel Therapeutic Antibodies for Cancer Therapy.

The activation of CD40-mediated signaling in antigen-presenting cells is a promising therapeutic strategy to promote immune responses against tumors. Most agonistic anti-CD40 antibodies currently in development require the Fcγ-receptor (FcγR)-mediated crosslinking of CD40 molecules for a meaningful activation of CD40 signaling but have limitations due to dose-limiting toxicities. Here we describe the identification of CD40 antibodies which strongly stimulate antigen-presenting cells in an entirely FcγR-independent manner.

Phenotyping of Macrophages in Human Immune System Mice.

Human immune system mice, also referred to as humanized mice, are a major research tool for the in vivo study of human immune system function. Upon reconstitution with human hematopoietic stem cells, all major human leukocyte populations develop in immunodeficient mice and can be detected in peripheral blood as well as in lymphatic and nonlymphatic tissue. This includes human macrophages that are intrinsically difficult to study from humans due to their organ-resident nature.

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment.

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy.

Modulation of urelumab glycosylation separates immune stimulatory activity from organ toxicity.

Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodies binding to cellular Fcγ-receptors (FcγR).

The Dual Targeting of FcRn and FcγRs Monomeric Fc Fragments Results in Strong Inhibition of IgG-Dependent Autoimmune Pathologies.

Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc gamma receptors (FcγRs) are emerging as promising treatments for immunoglobulin G (IgG)-dependent autoimmune pathologies. Mutated Fc regions and monoclonal antibodies that target FcRn are currently in clinical development and hold promise for reducing the levels of circulating IgG. Additionally, engineered structures containing multimeric Fc regions allow the dual targeting of FcRn and FcγRs; however, their tolerance needs to first be validated in phase I clinical studies.

Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in lyme arthritis.

Pathogen-specific antibody responses need to be tightly regulated to generate protective but limit self-reactive immune responses. While loss of humoral tolerance has been associated with microbial infections, the pathways involved in balancing protective versus autoreactive antibody responses in humans are incompletely understood. Studies in classical mouse model systems have provided evidence that balancing of immune responses through inhibitory receptors is an important quality control checkpoint.

HIF1A and NFAT5 coordinate Na-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting.

Infection and inflammation are able to induce diet-independent Na-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na-boosted host defense against the protozoan parasite is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against was neither dependent on NOS2 nor on the phagocyte oxidase.