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Background: alpha-Synuclein (alpha Syn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic alpha Syn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar alpha Syn, making UB-312 a potential immunotherapeutic for synucleopathies. Objective: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study. Methods: Fifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, double-blind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 mu g). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-aSyn antibody concentrations. Results: Twenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose- and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 mu g UB-312 dose regimen. The average CSF/serum ratio was 0.2%. Conclusions: UB-312 was generally safe, well tolerated, and induced anti-aSyn antibodies in serum and CSF of healthy participants. The 100 and 300 mu g doses are selected for further evaluation in participants with PD. (C) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Aims Keyhole limpet haemocyanin (KLH) immunization is a clinical model for the evaluation of human antibody responses. The current study evaluated the anti-KLH antibody response after KLH immunization and the delayed-type hypersensitivity response following intradermal KLH administration, using objective imaging techniques.Methods Healthy male subjects aged 24.5 +/- 5.4 years were randomized to intramuscular immunization with 100 mu g KLH (n = 12) or placebo (n = 3). Anti-KLH antibody (Ig) M and IgG titres were determined before and every 7 days after KLH immunization for a total of 28 days. Twenty-one days after the immunization, all subjects received 1 mu g KLH intradermally. Prior to and 2 days after intradermal KLH administration, skin blood perfusion, erythema and oedema were quantified using noninvasive imaging tools. Repeated measures ANCOVAs were used to analyse data.Results Anti-KLH IgM and IgG titres increased after KLH immunization compared to placebo (estimated difference [ED]: 37%, 95% confidence interval [CI]: 19-51% and ED: 68%, 95% CI: 56-76% respectively). Upon intradermal KLH administration an increase in skin blood perfusion (ED: 10.9 arbitrary units (AU), 95% CI: 1.4-20.4 AU) and erythema (ED: 0.3 AU, 95% CI: 0.1-0.5 AU) was observed in KLH-immunized subjects compared to placebo.Conclusion KLH immunization followed by intradermal KLH administration resulted in increased anti-KLH IgM and IgG titres and a delayed-type hypersensitivity response quantified by an increase in skin blood perfusion and erythema. Using noninvasive imaging tools the KLH model has the potential to serve as an objective tool to study the pharmacodynamics of T-cell-directed immunomodulatory drugs.

Imiquimod (IMQ) is often used as a topical challenge agent to provoke local skin inflammation. The objective of this study was to develop and refine a rapid, temporary, and reversible human skin inflammation model with IMQ for application in clinical drug development. A randomized, vehicle‐controlled, open‐label, dose‐ranging study was conducted in 16 healthy male subjects. IMQ (5 mg) was applied once daily for 72 hours under occlusion to intact skin (n = 8) or tape stripped (TS) skin (n = 8). Although IMQ alone induced limited effects, TS+IMQ treatment showed larger responses in several domains, including erythema and perfusion (P < 0.0001), mRNA expression of inflammatory markers (P < 0.01), and inflammatory cell influx compared with vehicle. In conclusion, a rapid, human IMQ skin inflammation challenge model was successfully developed with a clear benefit of TS prior to IMQ application. Future interaction studies will enable proof‐of‐pharmacology of novel compounds targeting the innate immune system.

The number of patients treated for prostate cancer by radiotherapy treatment has increased substantially over recent decades. However, after both external radiotherapy and brachytherapy, a subset of patients still develops recurrent disease during follow-up. In many patients these recurrences are often limited to one localisation in the prostate. In the past, on diagnosis of a recurrence, palliative hormonal treatment was started. Medical imaging by means of a CT scan was not adequate for delineating the recurrent lesion or for excluding metastases. In case where radiotherapy was considered the best treatment for the recurrence, this often resulted in serious adverse effects. Due to improvements in both imaging and radiotherapy techniques, it is now possible to target the local recurrent lesion only. In recurring prostate cancer this technique is known as focal salvage.