Biology subjects

Frendeus, B.

Publications and source records attributed to Frendeus, B..

3 recordsLinked to original sources

bioRxiv2025

Deletion or Targeted Blockade of FcγRIIb (CD32b) Impairs α-Syn Propagation In-Vivo

Parkinsons disease (PD), the most common neurodegenerative movement disorder, is characterised by pervasive deposition of alpha-synuclein (-Syn) aggregates and the death of dopaminergic neurons. Fc gamma receptor IIb (Fc{gamma}RIIb or CD32b), the sole inhibitory Fc{gamma}R in humans (h) and mice (m), serves as a molecular conduit for intercellular -Syn transmission in-vitro. Here, we demonstrate that Fc{gamma}RIIb facilitates -Syn propagation and neurotoxicity in-vivo using the pre-formed fibril (PFF) -Syn model in mice. Genetic ablation of mFc{gamma}RII attenuated PFF -Syn-induced Lewy pathology, dampened associated neuroinflammatory responses, and preserved nigrostriatal dopaminergic neurons. Furthermore, pharmacological blockade of hFc{gamma}RIIb using clinically-related monoclonal antibodies mitigated acute-phase -Syn pathology in hFc{gamma}RIIb-transgenic mice following PFF challenge. Collectively, our results indicate that Fc{gamma}RIIb is a mediator of -Syn propagation in-vivo and highlight it as a tractable therapeutic target against -synucleinopathies like PD.

neuroscience↗

bioRxiv2020

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Previous data suggests that anti-OX40 mAb can elicit anti-tumour effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. The contributions of these different effector mechanisms has not previously been systematically evaluated, particularly for mAb directed to human OX40. Therefore, we generated a novel human OX40 knock-in (KI) mouse to evaluate a panel of anti-hOX40 mAb and show that their activities relate directly to two key properties: 1) isotype – with mIgG1 mAb evoking receptor agonism and CD8+ T cell expansion and mIgG2a mAb evoking deletion of Treg and; 2) epitope - with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumour models by engaging these different mechanisms. These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T cell expansion or Treg depletion might be preferable according to the composition of different tumours.Summary Human trials with anti-OX40 antibodies have been disappointing indicating that optimal reagents have not yet been developed. Here, using a new panel of antibodies, we show that isotype and epitope combine to determine agonistic and therapeutic activity.Competing Interest StatementMSC is a retained consultant for BioInvent International and has performed educational and advisory roles for Baxalta and Boehringer Ingleheim. He has received research funding from Roche, Gilead, Bioinvent International and GSK. BF, IT, LM and MS are employees of Bioinvent International.View Full Text

immunology↗

bioRxiv2020

Activation of the myeloid checkpoint inhibitor LILRB3 (ILT5) elicits profound immununomodulation

Despite advances in identifying the key immunoregulatory roles of many of the human leukocyte immunoglobulin (Ig)-like receptor (LILR) family members, the function of the inhibitory molecule LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress for this receptor. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAb) was generated. LILBR3-specific mAb bound to discrete epitopes in either Ig-like domain two or four. LILRB3 ligation on primary human monocytes by agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responses in vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunosuppresive functions of LILRB3 and identify it as an important myeloid checkpoint receptor.

immunology↗