CBX7 inhibitors affect H3K9 methyltransferase-regulated gene repression in leukemic cells.

The epigenome of leukemic cells is dysregulated, and genes required for cell cycle arrest and differentiation may become repressed, which contributes to the accumulation of undifferentiated malignant blood cells. Here, we show that the Polycomb group protein CBX7 can interact with H3K9 methyltransferases EHMT1/2 and SETDB1. We aimed to assess whether combined interfering with these H3K9 methyltransferases and CBX7 could derepress target genes and thereby induce growth arrest of leukemic cells.

Continuity of Care and Lifestyle Intervention Programs for Spanish-Speaking Immigrants Without Health Insurance at a Free Clinic in Rhode Island.

Introduction: We conducted a retrospective cohort study to evaluate changes in metabolic biomarkers among participants in Bridging the [Health Equity] Gap (BTG), a free program run by Clínica Esperanza/Hope Clinic (CEHC) for Spanish-speaking immigrants without health insurance in Rhode Island.

Methods: From July 2019 through June 2021, 471 people volunteered to participate in the BTG program. Participants enrolled in lifestyle change classes and visited quarterly with health care providers.

Our Daughters-Ourselves: Evaluating the Impact of Paired Cervical Cancer Screening of Mothers with HPV Vaccination for Daughters to Improve HPV Vaccine Coverage in Bamako, Mali.

Cervical cancer (CC) is the second most common cancer in Western Africa, accounting for 12,000 cases and 6000 deaths annually. While vaccination against human papilloma virus (HPV) and CC screenings reduce the incidence and mortality of CC in many developed countries, 90% of CC deaths are in low-income countries. Lack of knowledge about the connection between HPV and CC, lack of access to vaccines and screenings, weak healthcare infrastructure, and stigma related to sexually transmitted diseases are among the factors that contribute to this disparity.

Assessing the immunogenicity risk of salmon calcitonin peptide impurities using and methods.

Advances in synthetic peptide synthesis have enabled rapid and cost-effective peptide drug manufacturing. For this reason, peptide drugs that were first produced using recombinant DNA (rDNA) technology are now being produced using solid- and liquid-phase peptide synthesis. While peptide synthesis has some advantages over rDNA expression methods, new peptide-related impurities that differ from the active pharmaceutical ingredient (API) may be generated during synthesis.

Individual and population-level variability in HLA-DR associated immunogenicity risk of biologics used for the treatment of rheumatoid arthritis.

Hypothesis: While conventional in silico immunogenicity risk assessments focus on measuring immunogenicity based on the potential of therapeutic proteins to be processed and presented by a global population-wide set of human leukocyte antigen (HLA) alleles to T cells, future refinements might adjust for HLA allele frequencies in different geographic regions or populations, as well for as individuals in those populations. Adjustment by HLA allele distribution may reveal risk patterns that are specific to population groups or individuals, which current methods that rely on global-population HLA prevalence may obscure.

Key Findings: This analysis uses HLA frequency-weighted binding predictions to define immunogenicity risk for global and sub-global populations.

In silico methods for immunogenicity risk assessment and human homology screening for therapeutic antibodies.

In silico immunogenicity risk assessment has been an important step in the development path for many biologic therapeutics, including monoclonal antibodies. Even if the source of a given biologic is 'fully human', T cell epitopes that are contained in the sequences of the biologic may activate the immune system, enabling the development of anti-drug antibodies that can reduce drug efficacy and may contribute to adverse events. Computational tools that identify T cell epitopes from primary amino acid sequences have been used to assess the immunogenic potential of therapeutic candidates for several decades.

How CBX proteins regulate normal and leukemic blood cells.

Hematopoietic stem cell (HSC) fate decisions are dictated by epigenetic landscapes. The Polycomb Repressive Complex 1 (PRC1) represses genes that induce differentiation, thereby maintaining HSC self-renewal. Depending on which chromobox (CBX) protein (CBX2, CBX4, CBX6, CBX7, or CBX8) is part of the PRC1 complex, HSC fate decisions differ.

Neoadjuvant personalized cancer vaccines: the final frontier?

Introduction: Clinical trials of personalized cancer vaccines have shown that on-demand therapies that are manufactured for each patient, result in activated T cell responses against individual tumor neoantigens. However, their use has been traditionally restricted to adjuvant settings and late-stage cancer therapy. There is growing support for the implementation of PCV earlier in the cancer therapy timeline, for reasons that will be discussed in this review.

A SARS-CoV-2 NSP7 homolog of a Treg epitope suppresses CD4+ and CD8+ T cell memory responses.

Pathogens escape host defenses by T-cell epitope mutation or deletion (immune escape) and by simulating the appearance of human T cell epitopes (immune camouflage). We identified a highly conserved, human-like T cell epitope in non-structural protein 7 (NSP7) of SARS-CoV-2, RNA-dependent RNA polymerase (RdRp) hetero-tetramer complex. Remarkably, this T cell epitope has significant homology to a T regulatory cell epitope (Tregitope) previously identified in the Fc region of human immunoglobulin G (IgG) (Tregitope 289).

Does human homology reduce the potential immunogenicity of non-antibody scaffolds?

Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on 'natural' protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have been developed.

Development of IFNβ-1a versions with reduced immunogenicity and full in vitro biological activity for the treatment of multiple sclerosis.

IFNβ (recombinant interferon Beta) has been widely used for the treatment of Multiple sclerosis for the last four decades. Despite the human origin of the IFNβ sequence, IFNβ is immunogenic, and unwanted immune responses in IFNβ-treated patients may compromise its efficacy and safety in the clinic. In this study, we applied the DeFT (De-immunization of Functional Therapeutics) approach to producing functional, de-immunized versions of IFNβ-1a.

Immunoinformatic Risk Assessment of Host Cell Proteins During Process Development for Biologic Therapeutics.

The identification and removal of host cell proteins (HCPs) from biologic products is a critical step in drug development. Despite recent improvements to purification processes, biologics such as monoclonal antibodies, enzyme replacement therapies, and vaccines that are manufactured in a range of cell lines and purified using diverse processes may contain HCP impurities, making it necessary for developers to identify and quantify impurities during process development for each drug product. HCPs that contain sequences that are less conserved with human homologs may be more immunogenic than those that are more conserved.

Optimization of therapeutic antibodies for reduced self-association and non-specific binding via interpretable machine learning.

Antibody development, delivery, and efficacy are influenced by antibody-antigen affinity interactions, off-target interactions that reduce antibody bioavailability and pharmacokinetics, and repulsive self-interactions that increase the stability of concentrated antibody formulations and reduce their corresponding viscosity. Yet identifying antibody variants with optimal combinations of these three types of interactions is challenging. Here we show that interpretable machine-learning classifiers, leveraging antibody structural features descriptive of their variable regions and trained on experimental data for a panel of 80 clinical-stage monoclonal antibodies, can identify antibodies with optimal combinations of low off-target binding in a common physiological-solution condition and low self-association in a common antibody-formulation condition.

Immunogenicity risk assessment of synthetic peptide drugs and their impurities.

Peptide drugs play an important part in medicine owing to their many therapeutic applications. Of the 80 peptide drugs approved for use in humans, at least five are now off-patent and are consequently being developed as generic alternatives to the originator products. To accelerate access to generic products, the FDA has proposed new regulatory pathways that do not require direct comparisons of generics to originators in clinical trials.

Specific sequence mutations in a long-lasting rhIFN-α2b version reduce and immunogenicity and increase protein stability.

For decades, recombinant human interferon alpha (rhIFN-α2b) has been used to treat emerging and chronic viral diseases. However, rhIFN-α2b is immunogenic and has a short half-life. To solve these limitations, two long-lasting hyperglycosylated proteins with reduced immunogenicity were developed and designated as 4N-IFN(VAR1) and 4N-IFN(VAR3).

Diversity and evolution of computationally predicted T cell epitopes against human respiratory syncytial virus.

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory infection. Despite more than 60 years of research, there is no licensed vaccine. While B cell response is a major focus for vaccine design, the T cell epitope profile of RSV is also important for vaccine development.

A story-telling cloth approach to motivating cervical cancer screening in Mali.

Ninety percent of deaths from Cervical cancer (CC) caused by Human Papilloma Virus (HPV) occur in low- and middle-income countries. CC is the 2nd most common cause of cancer in women in West Africa, where 12,000 women develop cervical cancer and more than 6,000 die from the disease, annually. While HPV vaccination and CC screening have dramatically reduced the incidence of CC and mortality from CC in developed countries, prevention of CC in West Africa is often limited to visual inspection of the cervix and surgical intervention.

Expanding access to COVID-19 testing, vaccination and treatment at a free clinic for uninsured Spanish-speaking adults in Providence, RI.

The COVID-19 pandemic disproportionately impacted uninsured and minority populations, contributing to and reinforcing long-lasting health inequities. Clínica Esperanza/Hope Clinic (CEHC), a free clinic serving uninsured individuals, is one 'safety-net' clinic that improved access to COVID-19 testing and vaccinations for an at-risk population during the pandemic. A retrospective review was performed to quantify COVID-19 testing and vaccination rates for clinic participants, which were compared to rates in the general population.

H1N1 G4 swine influenza T cell epitope analysis in swine and human vaccines and circulating strains uncovers potential risk to swine and humans.

Background: Pandemic influenza viruses may emerge from animal reservoirs and spread among humans in the absence of cross-reactive antibodies in the human population. Immune response to highly conserved T cell epitopes in vaccines may still reduce morbidity and limit the spread of the new virus even when cross-protective antibody responses are lacking.

Methods: We used an established epitope content prediction and comparison tool, Epitope Content Comparison (EpiCC), to assess the potential for emergent H1N1 G4 swine influenza A virus (G4) to impact swine and human populations.

Novel H7N9 influenza immunogen design enhances mobilization of seasonal influenza T cell memory in H3N2 pre-immune mice.

Strategies that improve influenza vaccine immunogenicity are critical for the development of vaccines for pandemic preparedness. Hemagglutinin (HA)-specific CD4 T cell epitopes support protective B cell responses against seasonal influenza. However, in the case of avian H7N9, which poses a pandemic threat, HA elicits only weak neutralizing antibody responses in infection and vaccination without adjuvant.

Durable antibody responses elicited by 1 dose of Ad26.COV2.S and substantial increase after boosting: 2 randomized clinical trials.

Background: Ad26.COV2.S is a well-tolerated and effective vaccine against COVID-19.

Meeting Gynecologic Needs and Assuring Adherence to Screening Guidelines at a Student-Run Free Clinic for Uninsured, Low-Income Women.

Background: Uninsured, low-income, Spanish-speaking patients face barriers to obtaining gynecologic care in the United States. Clínica Esperanza/Hope Clinic, a free clinic in Rhode Island, hosts a biweekly Women's Clinic (WC) established and run by local medical students.

Methods: A retrospective chart review identified gyne- cologic services provided, needs met and adherence to screening guidelines at WC between June 2017 and May 2021.