Peptides identified on monocyte-derived dendritic cells: a marker for clinical immunogenicity to FVIII products

The immunogenicity of protein therapeutics is an important safety and efficacy concern during drug development and regulation. Strategies to identify individuals and subpopulations at risk for an undesirable immune response represent an important unmet need. The major histocompatibility complex (MHC)–associated peptide proteomics (MAPPs) assay directly identifies the presence of peptides derived from a specific protein therapeutic on a donor’s MHC class II (MHC-II) proteins. We applied this technique to address several questions related to the use of factor VIII (FVIII) replacement therapy in the treatment of hemophilia A (HA). Although .12 FVIII therapeutics are marketed, most fall into 3 categories: (i) human plasma-derived FVIII (pdFVIII), (ii) full-length (FL)–recombinant FVIII (rFVIII; FL-rFVIII), and (iii) B-domain–deleted rFVIII. Here, we investigated whether there are differences between the FVIII peptides found on the MHC-II proteins of the same individual when incubated with these 3 classes. Based on several observational studies and a prospective, randomized, clinical trial showing that the originally approved rFVIII products may be more immunogenic than the pdFVIII products containing von Willebrand factor (VWF) in molar excess, it has been hypothesized that the pdFVIII molecules yield/ present fewer peptides (ie, potential T-cell epitopes). We have experimentally tested this hypothesis and found that dendritic cells from HA patients and healthy donors present fewer FVIII peptides when administered pdFVIII vs FL-rFVIII, despite both containing the same molar VWF excess. Our results support the hypothesis that synthesis of pdFVIII under physiological conditions could result in reduced heterogeneity and/or subtle differences in structure/conformation which, in turn, may result in reduced FVIII proteolytic processing relative to FL-rFVIII

Socio-demographic and health risk profile associated with participation in a private health insurance weight loss maintenance and chronic disease management program.

Objective Identifying who participates in chronic disease management programs yields insights into program reach and appeal. This study investigated sustained participation in a remotely delivered weight loss maintenance program offered to Australian private health insurance members. Methods All participants completing an initial 18-week weight loss program were eligible for a maintenance phase. A pre-post test design was used and sociodemographic and anthropometric characteristics of those who did and did not opt in to the maintenance phase were compared using binary logistic regression. Results Maintenance phase participants lost more weight during the initial weight loss program (−2.2 kg (P < 0.001); body mass index −0.8 kg/m2 (P < 0.001)) than those who did not opt in. Participants who were obese (v. overweight) upon completion of the initial weight loss program were less likely to opt in to the maintenance phase (adjusted odds ratio (aOR) 1.76, 95% confidence interval (CI) 1.35–2.30, P < 0.001) and participants aged ≥55 years were more likely to opt in (aOR 0.59, 95% CI 0.44–0.80, P < 0.001) than those aged <55 years. Conclusions Understanding why health insurance members opt in to maintenance programs can assist the development of strategies to improve program reach. Younger participants and those who remain obese following a weight loss program may be targeted by private health insurers and service providers to increase weight loss maintenance program participation. What is known about the topic? Australian private health insurers offer chronic disease management programs to support members to manage obesity-related chronic disease. An 18-week weight loss and lifestyle modification program was extended to assist participants maintain weight loss and health benefits resulting from the initial program. This weight loss maintenance phase is novel in the private health insurance setting and is thought to be important to sustained health improvement. Although program reach is important to benefit those most in need, little is known about who sustains the use (or does not) of such programs. What does this paper add? This study provides an insight to the characteristics of participants more likely to opt in to a weight loss maintenance program. It highlights the sociodemographic and anthropometric characteristics associated with maintenance program uptake, identifying the subgroups less likely to opt in. These study findings are novel because they report on participation in a chronic disease management program with a focus on maintenance of weight loss. What are the implications for practitioners? These results will benefit private health insurers and service providers implementing maintenance programs for weight loss, providing an awareness of which participant groups to target to increase maintenance and reach. In addition, they offer avenues for future exploration, such as the generalisability and sustainability of chronic disease management programs. Although those not opting in are a difficult-to-access group, a qualitative study of reasons for not opting in to such a program would provide further information for program design, recruitment and retention