TY - JOUR A1 - Lang, Isabell A1 - Zaitseva, Olena A1 - Wajant, Harald T1 - FcγRs and their relevance for the activity of anti-CD40 antibodies JF - International Journal of Molecular Sciences N2 - Simple Summary Targeting of CD40 with antibodies attracts significant translational interest. While inhibitory CD40 targeting appears particularly attractive in the field of organ transplantation and for the treatment of autoimmune diseases, stimulatory CD40 targeting is the aim in tumor immunotherapy and vaccination against infectious pathogens. It turned out that lack of FcγR-binding is the crucial factor for the development of safe and well-tolerated inhibitory anti-CD40 antibodies. In striking contrast, FcγR-binding is of great importance for the CD40 stimulatory capacity of the majority of anti-CD40 antibodies. Typically, anti-CD40 antibodies only robustly stimulate CD40 when presented by FcγRs. However, FcγR-binding of anti-CD40 antibodies also triggers unwanted activities such as destruction of CD40 expressing cells by ADCC or ADCP. Based on a brief discussion of the mechanisms of CD40 activation, we give an overview of the ongoing activities in the development of anti-CD40 antibodies under special consideration of attempts aimed at the development of anti-CD40 antibodies with FcγR-independent agonism or FcγR subtype selectivity. Abstract Inhibitory targeting of the CD40L-CD40 system is a promising therapeutic option in the field of organ transplantation and is also attractive in the treatment of autoimmune diseases. After early complex results with neutralizing CD40L antibodies, it turned out that lack of Fcγ receptor (FcγR)-binding is the crucial factor for the development of safe inhibitory antibodies targeting CD40L or CD40. Indeed, in recent years, blocking CD40 antibodies not interacting with FcγRs, has proven to be well tolerated in clinical studies and has shown initial clinical efficacy. Stimulation of CD40 is also of considerable therapeutic interest, especially in cancer immunotherapy. CD40 can be robustly activated by genetically engineered variants of soluble CD40L but also by anti-CD40 antibodies. However, the development of CD40L-based agonists is biotechnologically and pharmacokinetically challenging, and anti-CD40 antibodies typically display only strong agonism in complex with FcγRs or upon secondary crosslinking. The latter, however, typically results in poorly developable mixtures of molecule species of varying stoichiometry and FcγR-binding by anti-CD40 antibodies can elicit unwanted side effects such as antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) of CD40 expressing immune cells. Here, we summarize and compare strategies to overcome the unwanted target cell-destroying activity of anti-CD40-FcγR complexes, especially the use of FcγR type-specific mutants and the FcγR-independent cell surface anchoring of bispecific anti-CD40 fusion proteins. Especially, we discuss the therapeutic potential of these strategies in view of the emerging evidence for the dose-limiting activities of systemic CD40 engagement. KW - antibody fusion protein KW - CD40 KW - CD40L KW - cytokine storm KW - FcγR receptor KW - immunotherapy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290458 SN - 1422-0067 VL - 23 IS - 21 ER - TY - JOUR A1 - Solimando, Antonio Giovanni A1 - Kalogirou, Charis A1 - Krebs, Markus T1 - Angiogenesis as therapeutic target in metastatic prostate cancer – narrowing the gap between bench and bedside JF - Frontiers in Immunology N2 - Angiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has been extensively investigated as a promising druggable biological process. Nonetheless, targeting angiogenesis has failed to impact overall survival (OS) in patients with mCRPC despite promising preclinical and early clinical data. This discrepancy prompted a literature review highlighting the tumor heterogeneity and biological context of Prostate Cancer (PCa). Narrowing the gap between the bench and bedside appears critical for developing novel therapeutic strategies. Searching clinicaltrials.gov for studies examining angiogenesis inhibition in patients with PCa resulted in n=20 trials with specific angiogenesis inhibitors currently recruiting (as of September 2021). Moreover, several other compounds with known anti-angiogenic properties – such as Metformin or Curcumin – are currently investigated. In general, angiogenesis-targeting strategies in PCa include biomarker-guided treatment stratification – as well as combinatorial approaches. Beyond established angiogenesis inhibitors, PCa therapies aiming at PSMA (Prostate Specific Membrane Antigen) hold the promise to have a substantial anti-angiogenic effect – due to PSMA´s abundant expression in tumor vasculature. KW - prostate adenocarcinoma KW - PCa KW - angiogenesis inhibitors KW - TKI KW - immunotherapy KW - tumor microenvironment KW - clinical trials KW - PSMA Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-263061 SN - 1664-3224 VL - 13 ER - TY - JOUR A1 - Stoevesandt, Johanna A1 - Trautmann, Axel T1 - Risk factors in bee and Vespula venom allergy: state of the art JF - Allergo Journal International N2 - Background Correct recognition of risk factors enables individualized management and treatment of venom allergic patients. Methods Systematic research and review of current literature regarding the risk of (1) severe sting-induced anaphylaxis, (2) anaphylactic adverse event during venom immunotherapy (VIT), and (3) treatment failure. Results and discussion (1) Mastocytosis is the most important risk factor for severe sting-induced anaphylaxis. Hereditary α‑tryptasemia was recently identified as a genetic predictor of severe reactions. Older age is clearly associated with an increased risk; the respective impact of defined cardiovascular comorbidities has yet to be determined. Recent data do not support an aggravation of venom-induced anaphylaxis by intake of β‑blockers or angiotensin-converting enzyme (ACE) inhibitors. A higher risk in men can be attributed to more intensive exposure to stinging insects. (2) Anaphylactic side effects of VIT are most common during the buildup phase, particularly in the course of (ultra-)rush protocols involving a high number of injections and high cumulative daily doses. They are significantly more frequent during honeybee compared to Vespula VIT. Data supporting a negative effect of mastocytosis on the tolerability of VIT are scarce. Older age and cardiovascular medication are not associated with a higher incidence of VIT-induced anaphylaxis. (3) Relapsing anaphylactic reactions to both field and challenge stings are significantly more common during and after honeybee compared to Vespula VIT. Reports of severe field-sting reactions in mastocytosis patients suggest an increased risk of treatment failure which may be overcome by higher maintenance doses and longer duration of VIT. KW - mastocytosis KW - ACE inhibitor KW - age KW - Beta-blocker KW - hereditary alpha-tryptasemia KW - immunotherapy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270498 SN - 2197-0378 VL - 31 IS - 1 ER -