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The clinical performance of biological therapies is affected by their manufacturing processes. The advent of biosimilars increases the need to understand the clinical impact of potential differences versus originator products. We review important recently published technical data on adalimumab consistency and manufacturing experience from a clinical perspective, including the implications for immunogenicity when there are changes to a tightly controlled manufacturing process that may lead to variations in the epitopes of biological therapies. ispartof: GaBI - Generics and Biosimilars Initiative Journal vol:5 issue:2 pages:70-73 status: published

Humira® (adalimumab) is a recombinant human IgG1 monoclonal antibody (mAb) glycoprotein consisting of 1330 amino acids that is specific for human tumor necrosis factor (TNF). The biological activity and clinical profile of mAb therapeutics, including adalimumab, is influenced by their protein structure and glycosylation patterns, which can be affected by the expression system, cell culture conditions and purification process methodology. While clinical outcome cannot yet be attributed to many of the individual structural features that constitute a mAb, it is evident that detailed structural attribute analysis is necessary if structural contributions to function are to be comprehensively defined. Adalimumab product quality data generated from over a decade of manufacturing across multiple production sites and through a series of manufacturing scale changes are presented here. These data reveal a consistent and tightly controlled profile for the product.

This review delivers a commentary on the first decade of biologics’ use in psoriasis and provides a glimpse of the pipeline of therapies currently in development for psoriasis that will enhance the therapeutic armamentarium available to the dermatologist. In addition, the authors revisit the rationale for the development of biological therapies, inventory the available therapies of today, and retrospectively assess their impact on the dermatology practice as it relates to the management of patients with psoriasis.

Therapeutic agents with a putative anti-inflammatory mode of action are increasingly being pilot tested in psoriasis, a chronic inflammatory systemic disease. This is because the psoriasis patient contributes a number of advantages to trial design and execution (e.g., high disease prevalence, homogenous patient characteristics, skin manifestation that supports quick and easy quantification and viable placebo controls). Trial design for psoriasis is relatively standardized. Chronic plaque-type psoriasis usually follows a stable clinical course and also has well-accepted inclusion and exclusion criteria. Since psoriasis disease activity is characterized by lesions and percentage of the body area affected, there are multiple acceptable study end points that afford quantification of therapeutic impact, including quality of life, in the absence of a need for surrogate or biomarkers. Limitations of the psoriasis clinical trial framework are also apparent (e.g., multiple psoriasis phenotypes or capacity to evalu...

The International Psoriasis Council (IPC) is a global nonprofit organization dedicated to advancing psoriasis research and treatment by providing a forum for education, collaboration, and innovation among physicians, researchers, and other professionals interested in psoriasis. Each year, the IPC identifies the top papers in the field of psoriasis. Those selected from the second half of 2010 are reviewed here.

Research into all the relevant facets of disease characteristics—including epidemiology, genetics, and pathogenesis—has historically yielded important insights that result in a progression of understanding as well as advances in treatment of disease. Certainly psoriasis can be highlighted as an example of a disease that through history has benefitted from the integration of serendipitous observation and defined research strategy, an interaction that has resulted in dramatically improved clinical comprehension and management of the condition. Despite this progress, major gaps still exist in our understanding of the different elements of the disease that could be used to guide the medical community's approach to research. Traditionally, medical research is organized along geopolitical and departmental divisions. This structure tends to impede collaboration in a multidisciplinary manner or by multiple organizations working congruently. To overcome this impediment, the objective of this International Psoriasis Council initiative was to leverage the available knowledge to highlight the key research needs in psoriasis and to convene appropriate experts, without regard for geography or research specialty, to make major strides in improving the overall outcomes for psoriasis patients.

The International Psoriasis Council (IPC) is a global nonprofit organization dedicated to advancing psoriasis research and treatment by providing a forum for education, collaboration, and innovation among physicians, researchers, and other professionals interested in psoriasis. Each year, the IPC identifies the top papers in the field of psoriasis. They are reviewed here.

β–Defensin-2 Protein Is a Serum Biomarker for Disease Activity in Psoriasis and Reaches Biologically Relevant Concentrations in Lesional Skin

The Target Product Profile (TPP) is supposed to be the cornerstone of pharmaceutical product development. But how often is it utilized or updated, and how closely does it resemble the product that ...

In today's market, it is increasingly difficult for biopharmaceutical companies to commercialize products that realize a return on investment. This is because of a combination of escalating regulat...

Respiratory syncytial virus (RSV) is a major cause of respiratory tract disease in infants, aged adults, and immunosuppressed patients. The only approved medicines for RSV disease are administration of prophylatic antibodies or treatment with a synthetic nucleoside. Both approaches are expensive and the latter is not without risk and of controversial benefit. The present investigation studied whether pharmaceutical or biologic compounds based upon chemokines might be useful in preventing RSV disease. Of interest was RANTES/CCL5, which inhibits infection by HIV strains that use chemokine receptor (CCR)-5 as co-receptor. Herein, we report that prior or simultaneous treatment of HEp-2 cells with recombinant human CCL5 provides dose-dependent inhibition of infection with RSV. Other recombinant chemokines (MIP-1α/CCL3, MIP-1β/CCL4, MCP-2/CCL8, eotaxin/CCL11, MIP-1δ/CCL15, stromal cell derived factor (SDF)-1α/CXCL12) were not inhibitory. The data suggested that CCL5 might inhibit infection by blocking fusion (F) protein–epithelial cell interactions. Infections by mutant RSV strains deleted of small hydrophobic and/or attachment proteins and only expressing F protein in the envelope were inhibited by prior treatment with CCL5 or a biologically inactive N-terminally modified met-CCL5. Inhibition was also observed when virus adsorption and treatment with CCL5 were performed at 4°C. Flow cytometry further revealed that epithelial cells were positive for CCR3, but not CCR1 or CCR5. Thus, novel mimetics of CCL5 may be useful prophylatic agents to prevent respiratory tract disease caused by RSV. J. Med. Virol. 73:300–308, 2004. © 2004 Wiley-Liss, Inc.

Development of subunit vaccines against respiratory syncytial virus (RSV) for naive human infants is hindered by concerns that immunization with the fusion or attachment (G) proteins will elicit polarized Type 2 T cell responses and cause immunopotentiation upon subsequent natural infection. We investigated the regions of G protein responsible for inducing a Type 2 T cell phenotype in inbred mice of different MHC haplotype toward development of vaccines with improved safety. As demonstrated by IL-5-dependent pulmonary eosinophilia after challenge and serum anti-G protein IgG1 to IgG2 ratios, highly purified native G protein sensitized all strains for a Type 2 T cell phenotype. Stimulation of G protein-primed splenocytes with synthetic overlapping peptides indicated that the nonglycosylated ectodomain was primarily responsible. Respectively the recall responses of BALB/c (H2(d)), C57BL/6 (H-2(b)), SJL (H-2(s)), and C3H/HeJ (H-2(k)) mice were directed against epitopes within peptides spanning amino acids 184-198 (pep(184-198)), 168-181 (pep(168-181)) or 171-185 (pep(171-185)), 176-190 (pep(176-190)), and 104-118 (pep(104-118)) or 159-173 (pep(159-173)). Injection of pep(184-198) conjugated to KLH (pep(184-198)-KLH) primed H2(d) [BALB/c, B6.C-H2(d)/bBy], but not H-2(b) [C57Bl/6, C.B10-H2(b)/LiMcd] mice for pulmonary eosinophilia. Sensitization with a peptide-KLH conjugate encompassing amino acids 149-200 (pep(149-200)-KLH) further confirmed that Type 2 T cell responses in BALB/c, C57BL/6 and SJL, but not C3H/HeJ mice were induced by the nonglycosylated ectodomain of G protein. These data are important for design of safe and efficacious subunit and attenuated vaccines for RSV.

This review delivers a commentary on the first decade of biologics' use in psoriasis and provides a glimpse of the pipeline of therapies currently in development for psoriasis that will enhance the therapeutic armamentarium available to the dermatologist. In addition, the authors revisit the rationale for the development of biological therapies, inventory the available therapies of today, and retrospectively assess their impact on the dermatology practice as it relates to the management of patients with psoriasis.

The International Psoriasis Council, a global nonprofit organization dedicated to advancing psoriasis research and treatment, led an initiative to better define the association of various cardiometabolic comorbidities with psoriasis. In November 2013, a workshop was held in Boston, Mass. By assembling a panel of global dermatology, immunology, and cardiovascular experts, the objective was to better define the current status of the science that explains the association of psoriasis with various cardiometabolic-related comorbidities. The International Psoriasis Council has played a historical role in associating psoriasis with various comorbidities by integrating multidisciplinary expertise to advance the scientific and clinical knowledge through publications and clinical trials. This report synthesizes the current understanding of psoriasis with various cardiometabolic risk factors by exploring the potential shared pathogenic mechanisms and genetic connectivity.

In designing subunit vaccination strategies for respiratory syncytial virus (RSV), immunization by mucosal routes may present a realistic alternative to parenteral administration for inducing protective immune responses. To this end, we have utilized the BALB/c mouse model and an adjuvant formulation containing caprylic/capric glycerides (CCG) and polyoxyethylene-20-sorbitan monolaurate (PS). The intranasal (i.n.) delivery of purified natural F protein (3 microg per vaccine) formulated with CCG-PS resulted in the generation of statistically heightened serum anti-F protein immunoglobulin G (IgG), IgG1, IgG2b, and IgA antibodies. In addition, the presence of locally produced anti-F protein IgA was demonstrated in both vaginal and nasal washes of vaccinated mice. That production of specific serum and mucosal immunoglobulins resulted in functional immune responses was shown in neutralizing antibody assays and protection of mouse lungs against subsequent live virus challenge. Consequently, we propose a novel vaccine formulation composed of purified natural RSV F protein in CCG-PS as a viable intranasal immunogen to stimulate anti-RSV immune responses in humans.

We analyzed the immune responses evoked by a series of overlapping peptides to better understand the molecular basis for respiratory syncytial virus (RSV) G protein–induced eosinophilia in BALB/c mice. In vitro stimulation of spleen cells from natural G protein–primed mice showed dominant proliferative and cytokine (interferon [IFN]-γ and interleukin [IL]-5) responses to a peptide encompassing amino acids 184–198. Mice vaccinated with peptide 184– 198 conjugated to keyhole limpet hemocyanin showed significant pulmonary eosinophilia (39.5%) after challenge with live RSV. In contrast, mice immunized with a peptide (208–222) conjugate associated with induction of IFN-γ secreting spleen cells did not exhibit pulmonary eosinophilia after challenge. The in vivo depletion of CD4+ cells abrogated pulmonary eosinophilia in mice vaccinated with the peptide 184–198 conjugate, whereas the depletion of CD8+ cells had a negligible effect. Therefore, we have identified an association between peptide 184– 198 of natural G protein and the CD4+ T cell–mediated induction of pulmonary eosinophilia after live RSV challenge. Out of 43 human donors, 6 provided peripheral blood mononuclear cells that showed reactivity to G protein from RSV A2, 3 of which responded to peptide 184– 198. The results have important implications for the development of a vaccine against RSV.

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step in hepatic gluconeogenesis. Glucagon (via the second messenger cAMP), retinoic acid, and glucocorticoids stimulate transcription of the PEPCK gene, whereas insulin and phorbol esters have a dominant inhibitory effect. We now show that oxidative and chemical stress (hydrogen peroxide and sodium meta-arsenite, respectively) also produce a dominant inhibitory effect, both on the endogenous PEPCK gene and on a stably transfected PEPCK–chloramphenicol acetyl transferase (CAT) fusion gene. Wortmannin, an inhibitor of 1-phosphatidylinositol 3- kinase (PI 3-kinase), blocks the inhibition of glucocorticoid and cAMP-induced PEPCK gene transcription by insulin; however, it has no effect on the inhibition elicited by oxidative or chemical stress. Thus, the mechanism(s) used by hydrogen peroxide and sodium meta-arsenite to regulate PEPCK gene expression are PI 3-kinase independent. This suggests that these agents operate by a pathway distinct from that used by insulin or that the pathways converge at a point downstream of PI 3-kinase. The reactivating kinase (RK, also known as p38 mitogen activated protein kinase) is induced by insulin, hydrogen peroxide, or sodium metaarsenite in hepatoma cells, and these effects are blocked by SB203580, a selective inhibitor of RK. However, SB203580 has no effect on the ability of any of these agents to regulate PEPCK-CAT fusion gene expression. Thus, although RK has a role in the regulation of lymphokine gene expression in monocytes, it is not required for the regulation of PEPCK expression by either insulin or oxidative and chemical stress in hepatoma cells. From the Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, Tennessee.

The entry of biosimilar forms of biopharmaceutical therapies for the treatment of psoriasis and other immune-mediated disorders has provoked considerable interest. Although dermatologists are accustomed to the use of a wide range of generic topical agents, recognition of key differences between original agent (ie, the name brand) and the generic or biosimilar agent is necessary to support optimal therapy management and patient care. In this review we have summarized the current state of the art related to the impending introduction of biosimilars into dermatology. Biosimilars represent important interventions that are less expensive and hence offer the potential to deliver benefit to large numbers of patients who may not currently be able to access these therapies. But the development of biosimilars is not equivalent to that of small molecule generic therapies because of differences in molecular structure and processes of manufacture. The planned regulatory guidelines and path to approval may not encompass all of these potentially important differences and this may have clinical relevance to the prescriber and patient. Consequently, we have identified a series of key issues that should be considered to support the full potential of biosimilars for the treatment of psoriasis; ie, that of increased access to appropriate therapy for the psoriasis population worldwide.

Experts in psoriasis, hepatology, pharmacokinetics and pharmacogenetics convened to discuss the safety and monitoring of methotrexate with respect to hepatotoxicity when used in the treatment of psoriasis. Methotrexate is an efficacious and cost-effective treatment for psoriasis, but is associated with significant safety issues, particularly relating to hepatotoxicity. Current British, Dutch, German, EU and US guidelines for baseline evaluations, monitoring and prevention of hepatotoxicity in patients with psoriasis receiving methotrexate were evaluated. Liver safety monitoring is currently reliant upon multiple methods, including biopsy, serological tests for biomarkers such as type III procollagen amino terminal propeptide (PIIINP), and liver function tests based on liver enzymes. Monitoring of patients receiving long-term therapy is expected to be improved by the utilization of serum biomarkers currently in development such as the Enhanced Liver Fibrosis (ELF) panel and other non-invasive tests of hepatic architecture, such as fibroelastography, microbubbles and magnetic resonance imaging. Appropriate studies to determine optimal dosing to maximize efficacy and minimize toxicity, potentially utilizing pharmacogenetic principles, are clearly needed. Key questions for future research are identified including needs for optimal screening and monitoring, identification of appropriate biomarkers, assessment of relationships between dosing and safety, utility of liver biopsy, optimal dosing regimens (including route of administration), methods to measure methotrexate levels in blood, and use of methotrexate as a standardized active comparator in trials of experimental drugs used to treat psoriasis.

A history of acute bronchiolitis in infancy caused by respiratory syncytial virus is a risk factor for recurrent wheezing in early childhood. Because the attachment (G) protein sensitizes mice for pulmonary eosinophilia and because Th2 cells are central in the pathogenesis of asthma, plasma and peripheral blood mononuclear cells (PBMC) from donors with asthma and from healthy donors were evaluated for anti–G protein responses. A significant trend connecting severity of asthma with anti– G protein IgG1 and IgG2 titers was observed. The correlation between anti– F protein IgG3 titers and asthma severity approached significance. Peptide mapping studies revealed that more positive recall responses (interferon-g and interleukin-10 secretion) occurred after PBMC from donors with asthma were stimulated with peptides representing the nonglycosylated domain of G protein. The same peptides elicited more positive recall responses (proliferation and interferon-g secretion) in the PBMC of healthy donors. These data suggest that a mechanism may exist whereby adaptive immune responses against G protein contribute to wheezing. Asthma is an inflammatory disease of the airways that has a significant impact on health care costs in the United States [1]. One recognized factor contributing to asthma is viral infection of the lower respiratory tract [2]. For infants and toddlers, the virus most often associated with wheezing is respiratory syncytial virus (RSV). A recent review [3] of both prospective and retrospective studies that spanned several decades indicates that lower respiratory tract infection with RSV is a major risk factor for wheezing in children until age 11 years. RSV is an enveloped, negative-strand RNA pneumovirus estimated to cause as many as 90% of cases of bronchiolitis in infancy and 50% of all cases of pneumonia during the first 2 years of life [4].

We exploited the powerful adjuvant properties of cholera holotoxin (CT) to create a mucosally administered subunit vaccine against respiratory syncytial virus (RSV). A genetically detoxified mutant CT with an E to H substitution at amino acid 29 of the CT-A1 subunit (CT-E29H) was compared to wild type CT for toxicity and potential use as an intranasal (IN) adjuvant for the natural fusion (F) protein of RSV. When compared to CT the results demonstrated that: (1) CT-E29H binding to GM1 ganglioside was equivalent, (2) ADP-ribosylation of agmatine was 11.7%, and (3) toxicity was attenuated in both Y-1 adrenal (1.2%) and patent mouse gut weight assays. IN vaccination with F protein formulated with CT-E29H induced serum anti-CT and anti-F protein antibodies that were comparable to those obtained after vaccination with equivalent doses of CT. Vaccinations containing CT-E29H at doses of 0.1 microg were statistically equivalent to 1.0 microg in enhancing responses to F protein. Antigen-specific mucosal IgA and anti-RSV neutralizing antibodies were detected in nasal washes and sera, respectively, of mice that had received F protein and 0.1 or 1.0 microg of CT-E29H. Anti-F protein IgA was not detected in the nasal washes from mice IN vaccinated with 0.01 microg CT-E29H or IM with F protein adsorbed to AlOH adjuvant. In addition, the formulation of purified F protein and CT-E29H (0.1 and 1.0 microg) facilitated protection of both mouse lung and nose from live RSV challenge. Collectively, the data have important implications for vaccine strategies that use genetically detoxified mutant cholera holotoxins for the mucosal delivery of highly purified RSV antigens.