Showing papers in "BioDrugs in 2014"

Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab pegol.

Abstract: PEGylation of biological proteins, defined as the covalent conjugation of proteins with polyethylene glycol (PEG), leads to a number of biopharmaceutical improvements, including increased half-life, increased solubility and reduced aggregation, and reduced immunogenicity. Since their introduction in 1990, PEGylated proteins have significantly improved the management of various chronic diseases, including rheumatoid arthritis (RA) and Crohn’s disease. Certolizumab pegol is the only PEGylated anti-tumour necrosis factor (TNF)-α agent. It is a PEGylated, humanised, antigen-binding fragment of an anti-TNF monoclonal antibody. Unlike other anti-TNF agents, it has no crystallisable fragment (Fc) domain. Because of its novel structure, certolizumab pegol may have a different mechanism of action to the other anti-TNF agents, and also has different pharmacodynamic properties, which could possibly translate to a different safety profile. Pharmacodynamic studies have shown that certolizumab pegol binds to TNF with a higher affinity than adalimumab and infliximab. Certolizumab pegol is also more potent at neutralising soluble TNF-mediated signalling than adalimumab and infliximab, and has similar or lesser potency to etanercept. Certolizumab pegol does not cause detrimental in vitro effects such as degranulation, loss of cell integrity, apoptosis, complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Certolizumab pegol may also penetrate more effectively into inflamed arthritic tissue than other anti-TNF agents, and is not actively transported across the placenta during pregnancy. Pharmacokinetic studies in healthy volunteers demonstrated that single intravenous and subcutaneous doses of certolizumab pegol had predictable pharmacokinetics. The pharmacokinetics of certolizumab pegol in patients with RA and Crohn’s disease were consistent with pharmacokinetics in healthy volunteers.

Bacteriophage Polysaccharide Depolymerases and Biomedical Applications

Abstract: Polysaccharide depolymerase, a polysaccharide hydrolase encoded by bacteriophages (or 'phages'), can specifically degrade the macromolecule carbohydrates of the host bacterial envelope. This enzyme assists the bacteriophage in adsorbing, invading, and disintegrating the host bacteria. Polysaccharide depolymerase activity continues even within biofilms. This effectiveness means phages are promising candidates for novel antibiotic scaffolds. A comprehensive compendium of bacteriophage polysaccharide depolymerases has been compiled, together with their potential biomedical applications, such as novel antibiotics, adjuvants for antibiotics, bacterial biofilm disruptants, and diagnostic kits.

Drift, Evolution, and Divergence in Biologics and Biosimilars Manufacturing

Abstract: Biological medicines (biologics) are produced in living cells and purified in complex, multi-step processes. Compared with chemically synthesized small-molecule drugs, biologics are more sensitive to changes in manufacturing conditions. Process and product consistency should be founded on rigorous design and control of manufacturing processes, but consistency is ultimately ensured through robust quality systems. Even a minor change in any component of a quality system could lead to product drift, evolution, and divergence, which may impact the quality, safety, efficacy, and/or interchangeability of biologics. Unintended or unexplained deviations in manufacturing processes can lead to excursions in product attributes (i.e., drift). Well-managed quality systems can help detect and mitigate drift. Occasionally, quality attributes could shift outside of established acceptable ranges as the result of a known manufacturing change (defined here as evolution). Such changes should be studied extensively for effects on product safety and efficacy. With the advent of biosimilars, similar biologics will be produced by multiple manufacturers with different quality systems. Different patterns of product drift and evolution could contribute, over time, to clinically meaningful differences among biologics, including among originator products across regions and among originator products and biosimilar products, a process defined here as divergence. Manufacturers and policymakers can minimize the potential impact of divergence by establishing robust pharmacovigilance systems; requiring distinguishable names for all biologics, including both originator products and biosimilars; adhering to high standards for designations of interchangeability; and ensuring that patient medical records accurately reflect the specific biologic dispensed, especially if the biologic could be sourced from multiple manufacturers.

A Review of CT-P13: An Infliximab Biosimilar

Abstract: CT-P13 (Remsima™; Inflectra™), a biosimilar of reference infliximab (Remicade(®)), is approved by the European Medicines Agency for use in all indications for which reference infliximab is approved, including rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriatic arthritis and psoriasis Infliximab is a chimeric human-murine monoclonal antibody against the proinflammatory cytokine tumour necrosis factor-α The CT-P13 infliximab formulation is identical to that of reference infliximab and it has similar physiochemical characteristics The approval of CT-P13 was based on the results of a rigorous, comparability exercise This article reviews the results of that exercise, focusing on the clinical evaluation programme In two well-designed clinical trials, CT-P13 was equivalent to reference infliximab in terms of pharmacokinetic properties in patients with ankylosing spondylitis and in terms of efficacy in patients with rheumatoid arthritis In both studies, CT-P13 was generally well tolerated with a similar tolerability profile to that of reference infliximab Immunogenicity evaluations demonstrated that the proportion of patients developing anti-drug antibodies was similar with each agent Preliminary data from trial extensions demonstrated that in patients who switched from reference infliximab to CT-P13, efficacy was sustained and similar to those who were treated continuously with CT-P13 As with all biosimilar and generic agents, CT-P13 has the potential to reduce treatment costs compared with those of reference infliximab, and modelled analyses predict significant cost savings compared with reference infliximab In conclusion, CT-P13 is an infliximab biosimilar that provides a useful alternative to reference infliximab in patients requiring infliximab therapy

Targeting survivin in cancer: novel drug development approaches.

Abstract: Survivin is a well-established target in experimental cancer therapy. The molecule is over-expressed in most human tumors, but hardly detectable in normal tissues. Multiple functions in different subcellular compartments have been assigned. It participates in the control of cell division, apoptosis, the cellular stress response, and also in the regulation of cell migration and metastasis. Survivin expression has been recognized as a biomarker: high expression indicates an unfavorable prognosis and resistance to chemotherapeutic agents and radiation treatment. Survivin is an unconventional drug target and several indirect approaches have been exploited to affect its function and the phenotype of survivin-expressing cells. Interference with the expression of the survivin gene, the utilization of its messenger RNA, the intracellular localization, the interaction with binding partners, the stability of the survivin protein, and the induction of survivin-specific immune responses have been taken into consideration. A direct strategy to inhibit survivin has been based on the identification of a specifically interacting peptide. This peptide can recognize survivin intracellularly and cause the degradation of the ligand–survivin complex. Technology is being developed that might allow the derivation of small molecular-weight, drug-like compounds that are functionally equivalent to the peptide ligand.

Safety and Pharmacokinetics of Escalating Doses of Human Recombinant Nerve Growth Factor Eye Drops in a Double-Masked, Randomized Clinical Trial

Abstract: Background and Objectives Nerve growth factor (NGF) is a neurotrophin with therapeutic possibilities that extend from the nervous system to the eye. We tested the safety, maximal tolerated dose, pharmacokinetics, and antigenicity of a novel human recombinant NGF (rhNGF) eye-drop formulation in a phase I study.

Recent advances on host plants and expression cassettes' structure and function in plant molecular pharming

Abstract: Plant molecular pharming is a promising system to produce important recombinant proteins such as therapeutic antibodies, pharmaceuticals, enzymes, growth factors, and vaccines. The system provides an interesting alternative method to the direct extraction of proteins from inappropriate source material while offering the possibility to overcome problems related to product safety and source availability. Multiple factors including plant hosts, genes of interest, expression vector cassettes, and extraction and purification techniques play important roles in the plant molecular pharming. Plant species, as a biosynthesis platform, are a crucial factor in achieving high yields of recombinant protein in plant. The choice of recombinant gene and its expression strategy is also of great importance in ensuring a high amount of the recombinant proteins. Many studies have been conducted to improve expression, accumulation, and purification of the recombinant protein from molecular pharming systems. Re-engineered vectors and expression cassettes are also pivotal tools in enhancing gene expression at the transcription and translation level, and increasing protein accumulation, stability, retention and targeting of specific organelles. In this review, we report recent advances and strategies of plant molecular pharming while focusing on the choice of plant hosts and the role of some molecular pharming elements and approaches: promoters, codon optimization, signal sequences, and peptides used for upstream design, purification and downstream processing.

Drug Desensitization in the Management of Hypersensitivity Reactions to Monoclonal Antibodies and Chemotherapy

Abstract: Hypersensitivity reactions to monoclonal antibodies and chemotherapy, which may vary in severity from mild to life-threatening, can lead to their discontinuation and replacement by alternative agents that are often less effective, more toxic, and/or more expensive. Drug desensitization has emerged as the best treatment modality capable of allowing re-introduction of the hypersensitivity reaction-inducing medication in highly sensitized patients in need of first line therapies. In recent years, the availability of new anti-neoplastic drugs and therapeutic monoclonal antibodies has increased, as has the potential for hypersensitivity reactions. Development of desensitization protocols for these new medications requires a careful assessment of the potential risks and benefits. The purposes of this review are to provide an overview of the presentation of hypersensitivity reactions amenable to desensitization and to increase awareness of the indications for and outcomes of desensitization protocols. Rapid drug desensitization has proven to be a safe and effective way of administering first line therapy to patients with hypersensitivity reactions, providing an extremely powerful treatment modality for patients for whom alternative drugs are deemed unacceptable. Rapid drug desensitization protocols should be administered only by highly trained allergists and nurses who have experience in determining which reactions are amenable to desensitization, and can identify high risk patients and provide them with appropriate care. Efforts should be made to increase awareness of the remarkable safety and efficacy of rapid drug desensitization among non-allergists, especially in the fields of oncology and rheumatology, so as to favor its universal application. Development of desensitization units to provide state-of-the-art care is possible only through coordinated teamwork.

Comparative Nonclinical Assessments of the Proposed Biosimilar PF-05280014 and Trastuzumab (Herceptin®)

Abstract: Background and Objectives Trastuzumab (Herceptin®) is a humanized monoclonal antibody (mAb) that binds to the HER2 protein. PF-05280014 is being developed as a potential biosimilar to trastuzumab products marketed in the United States (trastuzumab-US) and European Union (trastuzumab-EU). Nonclinical studies were designed to evaluate the similarity of PF-05280014 to trastuzumab-US and trastuzumab-EU using in vitro structural and functional analyses, and in vivo pharmacokinetic and immunogenicity assessments.

The role of interleukin-17A in psoriatic disease.

Abstract: The pathogenic mechanisms of specific immune-mediated inflammatory diseases (IMIDs) are not fully understood, but are thought to involve activated T cells with the release of pro-inflammatory cytokines. Understanding the autoimmune inflammatory pathways has led to the development of biological agents that target specific components of effector immune mechanisms. Despite the availability of many effective drugs, a large proportion of patients with moderate to severe IMID do not receive adequate treatment, and many therapies show decreased efficacy over time. Therefore, there is a need for new therapies. One subset of T helper cells, Th17, and the cytokine interleukin-17 (IL-17) play a central role in the pathophysiology of autoimmune diseases such as psoriasis. IL-17 is involved in the modulation of pro-inflammatory cytokines, haematopoietic growth factors, antimicrobial peptides, chemokines, and molecules involved in tissue remodelling; the inflammatory cascades triggered by Th17 cells and IL-17 itself, when unregulated, can result in widespread inflammation-related damage. Evidence of increased Th17 activity and high levels of IL-17 has been found in psoriasis, as well as other inflammatory conditions, thereby signalling the potential utility of IL-17 as a therapeutic target. Clinical trials investigating IL-17 inhibitors, such as secukinumab, in patients with psoriatic disease have reported no significant safety concerns so far. It is hoped that these agents will improve the long-term prognosis of patients with these debilitating disorders.

CD30 as a therapeutic target for lymphoma.

Abstract: Hodgkin’s lymphoma (HL) and ALK+ anaplastic large-cell lymphoma (ALCL) have become highly curable due to the success of modern regimens of chemotherapy and radiotherapy. However, up to one-third of the patients experience relapse or do not respond to first-line therapy, and half of them relapse again after secondary therapy with limited options for further treatment. In the last 15 years, monoclonal antibodies (mAbs) directed to surface receptors became a new and valuable therapeutic option in many hematologic malignancies. Due to its restricted expression on normal activated lymphocytes and its high expression on malignant cells, CD30 represents an attractive target molecule for HL and ALCL therapy. However, unconjugated CD30 mAbs have demonstrated a lack of objective clinical responses in patients with recurrent HL. CD30 exhibits complex signaling pathways, and binding of its natural ligand or anti-CD30 mAbs can induce apoptosis but may also promote proliferation and activation depending on the cellular context. Moreover, CD30 rapidly internalizes after crosslinking, which counteracts efficient recruitment of immunologic effectors but also provides the opportunity to transfer cytotoxic payloads coupled to CD30-specific mAbs into the tumor cells. Several tumor targeting approaches have been studied, including radio-immunoconjugates, immunotoxins, immunoRNases, immunokinases, and antibody drug conjugates (ADCs). In 2011, the ADC brentuximab-vedotin, consisting of the CD30-specific chimeric mAb cAC10 and the potent tubulin toxin monomethyl auristatin E, gained regulatory approval as a well tolerated and highly active drug in patients with refractory and relapsed HL and ALCL. SGN-35 is on the way to being incorporated in the standard management of CD30+ lymphoma with significant therapeutic impact. This review gives a critical overview about anti-CD30 therapies with unconjugated, engineered, and conjugated mAbs and the therapeutic challenges of treatment of CD30+ lymphoma.

miR-125b Inhibitor May Enhance the Invasion-Prevention Activity of Temozolomide in Glioblastoma Stem Cells by Targeting PIAS3

Abstract: Background Temozolomide, an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. Although chemotherapy with temozolomide may restrain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells maintaining these tumors persist. Previous research has shown that temozolomide can inhibit the proliferation of human glioblastoma stem cells (GSCs); however, no research has focused on the invasion of GSCs, which is an important factor for glioblastoma recurrence. Accumulating evidence indicates that microRNA (miR)-125b over-expression in GSCs may increase their invasiveness.

Efficacy and Safety of Biologic Therapies for Systemic Lupus Erythematosus Treatment: Systematic Review and Meta-Analysis

Abstract: The objectives of this study were to evaluate the efficacy, safety, and tolerability of biologic drugs compared with placebo for systemic lupus erythematosus (SLE) treatment. A systematic review evaluating the efficacy and safety of biologic therapies compared with placebo in adult SLE patients treatment was performed. Data from studies performed before September 2013 were collected from several databases (MEDLINE, Cochrane Library, SCIELO, Scopus, and International Pharmaceutical Abstracts). Study eligibility criteria included randomized, double-blind, placebo-controlled trials; regarding treatment with biologic agents in SLE adult patients; and published in English, German, Portuguese, and Spanish. Extracted data were statistically analyzed in a meta-analysis using the Review Manager (RevMan) 5.1 software. Efficacy outcomes included the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index) score, the SRI (Systemic Lupus Erythematosus Responder Index), normalization of low C3 (<90 mg/dL), anti-double-stranded DNA positive to negative, and no new BILAG (British Isles Lupus Assessment Group index) 1A or 2B flares. Data on safety profile included adverse events, serious and severe adverse events, death, malignancy, infections, and infusion reactions. We also evaluated withdrawals from treatment due to lack of efficacy or adverse events. Thirteen randomized placebo-controlled trials met the criteria for data extraction for systematic review. A meta-analysis regarding the efficacy and safety of belimumab compared with placebo involving four of these trials was undertaken and the remainder contributed to a meta-analysis of the safety of biologic agents. In addition, two trials allowed the performance of a meta-analysis regarding the efficacy and safety of rituximab compared with placebo. Belimumab was more effective than placebo in most evaluated outcomes. No significant differences in the safety and tolerability data were observed between the belimumab and placebo groups. No differences were observed between the rituximab and placebo groups for the efficacy outcomes or safety parameters. Extracted data from the 13 studies were pooled, allowing assessment of the safety of biologic drugs. The meta-analysis revealed a satisfactory safety profile of these agents when used for SLE treatment, as there were no significant differences between the two evaluated groups (biologic agents and placebo) for all outcomes analyzed. Belimumab exhibited a satisfactory profile regarding efficacy, safety, and tolerability. Rituximab showed no superiority over placebo in terms of efficacy, despite its suitable safety profile. Biologic agents exhibited a good safety profile for SLE treatment, indicating that these agents are promising therapies and should be further investigated.

Intravenous Tocilizumab: A Review of Its Use in Adults with Rheumatoid Arthritis

Abstract: Tocilizumab (Actemra®, RoActemra®) is a humanized monoclonal antibody that acts as an interleukin-6 receptor antagonist. Intravenous tocilizumab as monotherapy or in combination with disease-modifying anti-rheumatic drugs (DMARDs) is indicated for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA) who had an inadequate response to one or more DMARDs or tumor necrosis factor (TNF) α antagonists (the specific indication varies between countries); it may also be used as monotherapy in patients for whom continued methotrexate use is inappropriate. This article reviews the efficacy and tolerability of tocilizumab in these patients and briefly summarizes its pharmacology. Several large well-designed clinical trials and routine clinical practice studies showed that tocilizumab was an effective and generally well tolerated biologic for the treatment of adults with RA, including those with an inadequate response to DMARDs or TNFα antagonists. In these studies, tocilizumab as monotherapy or in combination with DMARDs (including methotrexate) had beneficial effects on the signs and symptoms of disease, health-related quality of life/physical function, and/or radiologic disease progression. In addition, tocilizumab monotherapy was more effective than adalimumab monotherapy in improving the signs and symptoms of disease in patients for whom continued methotrexate use was inappropriate. As with other biologic DMARDS, infections were the most common adverse event associated with tocilizumab therapy. Pooled and meta-analyses demonstrated that the efficacy and tolerability profile of tocilizumab was sustained during long-term (up to 9 years) therapy. Although additional comparative data are needed to position tocilizumab more definitively with respect to other biologic DMARDs, current evidence indicates that tocilizumab is effective as a first- or subsequent-line biologic in patients with moderate to severe RA.

Tumor-Infiltrating Lymphocyte Therapy for Melanoma: Rationale and Issues for Further Clinical Development

Abstract: Cancer immunotherapy has become an important area for the future development of cancer therapy; this includes T-cell-based therapies that involve adoptive transfer of autologous T cells derived from the tumors or peripheral blood of cancer patients, vaccines, oncolytic virus therapy, and immunomodulatory antibodies and ligands. Here, we summarize the current approaches and clinical data in the field of adoptive T-cell transfer therapy using tumor-infiltrating lymphocytes (TILs) for metastatic melanoma. We also discuss current knowledge on the mechanism of transferred TILs in mediating tumor regression and the growing need for and recent advances in the identification of predictive biomarkers to better select patients for TIL therapy. The current technical limitations of current TIL expansion methods for out-scaling are discussed as well as how these are being addressed in order to further “industrialize” this form of cell therapy. Lastly, how TIL adoptive transfer can be incorporated into the current melanoma treatment continuum, especially as combination therapy with other immunomodulators and targeted drugs, is discussed.

The Cost Effectiveness of Biologic Therapy for the Treatment of Chronic Plaque Psoriasis in Real Practice Settings in Italy

Abstract: Biologic therapies are considered to be cost effective by leading Health Technology Assessment (HTA) agencies and, therefore, eligible for reimbursement by public health services. However, biologic therapies entail sizable incremental costs and, besides, have a considerable financial impact that in Italy amounts to 13.7 % of the national health service’s pharmaceutical expenditure. In the reimbursability decision process, an important role is played by both the drug efficacy data observed in pre-licensing RCTs and the economic modelling assumptions, as they give evidence on cost effectiveness. The administration of therapies in real practice settings is likely to produce a significant deviation from the results predicted by the models, theoretically outweighing the assumption on which the decision process is founded. This is a matter of concern for public health services and, consequently, an interesting topic to investigate. To overcome the lack of knowledge concerning the actual cost effectiveness of biologic therapies for the treatment of plaque psoriasis in the clinical practice setting in Italy, an observational study was conducted in 12 specialist centres on patients switching to biologic therapy within a 6-month enrolment window. The study confirms in clinical practice the efficacy of the switch to biologic therapies, analysed using a number of clinical [Psoriasis Area and Severity Index (PASI), pain visual analogue scale (VAS) and itching VAS] and quality-of-life parameters. A general health-related quality of life (HR-QOL) improvement, with a 0.23 quality-adjusted life-year (QALY) mean gain per patient, has been reported in the 6-month observation period. The direct medical costs to treat plaque psoriasis with biologic therapies amount to €15,073.7 per year (prior to their enrolment, the same patients cost €2,166.2 on an annual basis). After the switch to biologic agents, the cost per QALY during the first year of treatment amounts to €28,656.3. At least in the short-term, the clinical practice of the specialised Italian centres taking part in the study confirms that switching patients to a biologic drug produces an incremental cost-effectiveness ratio comparable with the values predicted by the HTA bodies.

Tumour necrosis factor α antagonists in the treatment of rheumatoid arthritis: An immunological perspective

Abstract: Rheumatoid arthritis (RA) is one of the most prevalent autoimmune conditions, affecting approximately 1 % of the adult population. It is associated with decreased quality of life and considerable morbidity and mortality. Various inflammatory cells, including macrophages, neutrophils, mast cells, natural killer cells, B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression. Several cytokines, including interleukin (IL)-1α and/or IL-1β, and tumour necrosis factor (TNF)-α, are involved at each stage of RA pathogenesis; namely, by augmenting autoimmunity, sustaining long-term inflammatory synovitis and promoting joint damage. Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro-inflammatory mediators. As early as the late 1980s, TNF had been identified as a potential target in RA. Five anti-TNF drugs, infliximab, adalimumab, certolizumab pegol, etanercept and golimumab, are now approved for the treatment of RA in various countries. All are bivalent monoclonal antibodies, with the exception of the monovalent certolizumab and etanercept, which is an engineered dimeric receptor. Although all react with and neutralise soluble TNF in vitro, structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects. Pegylated certolizumab permits once-monthly dosing. Other mechanisms of action proposed to be important for the efficacy of anti-TNF agents are as follows: induction of apoptosis of both monocytes and T cells; neutralization of membrane TNF; antibody-dependent cell-mediated and complement-dependent cytotoxicity; and reverse signaling via membrane TNF.

Elosulfase Alfa: A Review of Its Use in Patients with Mucopolysaccharidosis Type IVA (Morquio A Syndrome)

Abstract: Elosulfase alfa (Vimizim®) is a recombinant form of the human lysosomal enzyme N-acetylgalactosamine-6-sulfatase (GALNS) that is lacking in patients with mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome). It is the first, and currently only, disease-specific treatment option for this very rare, progressively degenerative, autosomal-recessive lysosomal storage disorder. Enzyme replacement therapy with elosulfase alfa aims to restore GALNS activity, thereby preventing the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate in lysosomal compartments of cells that results in the clinical manifestations of MPS IVA. In clinical trials in children and adults with MPS IVA, intravenous elosulfase alfa 2 mg/kg/week provided significant and sustained improvements in urinary levels of KS (a pharmacodynamic biomarker for the disease). In the key placebo-controlled, 24-week, phase 3 trial in patients with MPS IVA aged ≥5 years, elosulfase alfa 2 mg/kg/week significantly improved endurance [least squares mean placebo-adjusted change from baseline in 6-min walk test distance 22.5 m (95 % CI 4.0–40.9)]. Infusion-associated reactions, the primary tolerability issue associated with elosulfase alfa, are generally mild to moderate in severity, self-limiting, and manageable. In the absence of a cure, GALNS enzyme replacement therapy with elosulfase alfa is an important achievement in the treatment of MPS IVA.

Second-Generation Tyrosine Kinase Inhibitors in First-Line Treatment of Chronic Myeloid Leukaemia (CML)

Abstract: Tyrosine kinase inhibitors (TKIs) have contributed to marked improvements in survival in patients with chronic myeloid leukaemia (CML). This article discusses the place of the second-generation TKIs dasatinib and nilotinib in the first-line treatment of CML and is based on published literature. The new agents are more potent and effective than imatinib. Data from pivotal clinical trials indicate that response to dasatinib and nilotinib is greater and more rapid than that to imatinib, resulting in a higher probability of patients achieving an optimal response to treatment. Differences between the newer agents with respect to patient groups for whom caution is advised, drug interaction potential, haematological toxicity, pulmonary toxicity, changes in the immune system and effects on laboratory parameters are discussed. With similar levels of efficacy, the choice of second-generation agents should be guided by the characteristics of the individual patient and the most suitable dosing regimen.

Targeting the PI3K/Akt/mTOR pathway in malignancy: rationale and clinical outlook

Abstract: The phosphatidylinositol 3-kinase (PI3K) pathway, including major downstream effectors Akt and mammalian target of rapamycin (mTOR), plays a critical role in malignant transformation and subsequent processes of growth, proliferation, and metastases. Not surprisingly, the PI3K/Akt/mTOR pathway has emerged as an attractive drug target and numerous agents directed against various elements of the pathway are currently in clinical development. While early clinical trials with the first generations of these agents have shown limited single-agent efficacy, efforts are now focused on the development of more specific inhibitors, patient selection strategies, and combinational approaches. In this review, we discuss the PI3K/Akt/mTOR pathway in cancer, the rationale for its emergence as a therapeutic target, and progress thus far in the clinical development of inhibitors targeting its various elements.

Management of Metastatic Breast Cancer With Second-Generation Antibody-Drug Conjugates: Focus on Glembatumumab Vedotin (CDX-011, CR011-vcMMAE)

Abstract: Exploiting the highly targeted nature of monoclonal antibodies to deliver selectively to tumor cells a cytotoxic payload is an attractive concept and the successful precedents of the recent past set the stage for broader applications in the future. Antibody–drug conjugates may currently hold an unprecedented potential; however, there are multiple unique challenges in their development, and the recent successes have come hand in hand with significant technologic advances in their chemistry and manufacturing. Over the years, multiple factors have been identified to affect the pharmacokinetic and pharmacodynamic properties of an antibody–drug conjugate, but many important details remain to be further investigated. These factors pertain to the target antigen, antibody, conjugate, linker, as well as the nature of the malignancy under treatment. Glembatumumab vedotin is an antibody–drug conjugate targeting glycoprotein non-metastatic B (GPNMB) expressed in multiple malignancies, including breast cancer. The expression of this protein has been associated with an aggressive malignant phenotype, invasive growth, angiogenesis, and generation of skeletal metastases. Glembatumumab vedotin is currently in early stages of clinical development in melanoma and breast cancer. Although in unselected patients with metastatic breast cancer glembatumumab vedotin was not superior to other agents, by virtue of its target being frequently and highly expressed in triple-negative breast cancer, its activity was particularly promising in this subset of patients. Results from the clinical studies in breast cancer as well as companion studies in melanoma indicate that a biomarker-informed approach is the optimal pathway for the future development of this drug.

Genetically Engineered Humanized Mouse Models for Preclinical Antibody Studies

Abstract: The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene-editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies.

Practical Considerations for the Pharmacokinetic and Immunogenic Assessment of Antibody–Drug Conjugates

Abstract: Currently, the most bioanalytically challenging drugs are antibody–drug conjugates (ADCs), constructs comprising a monoclonal antibody and a cytotoxic drug connected by a linker. The bioanalytical challenges arise from the heterogeneous nature of ADCs and their complex in vivo behavior, resulting in a high number of analytes to be measured. Measuring the concentration of biologics in blood/plasma/serum is a necessity to properly assess their pharmacokinetic (PK)/pharmacodynamic behaviors in vivo. An additional bioanalytical challenge is to monitor the stability of the ADCs, as cytotoxic drugs released from the ADC in blood circulation may pose a potential safety risk because of their high cytotoxic potency. The nature of ADCs does not only complicate bioanalysis, but also immunogenicity assessment. Questions, such as ‘Which part of the ADCs is the anti-drug antibodies directed against?’ may arise, and their answer normally includes several immunogenicity risk assessment strategies. This review will focus on the bioanalytical challenges of ADCs, current approaches involving ligand-binding assays (LBAs), liquid chromatography and mass spectrometry platforms, and recommendations on which approach to use for which stage of drug development, and will close with immunogenicity assessment. In order to appropriately tackle the bioanalytical and immunogenic challenges of ADCs and consider every angle, the authors of this review have expertise in ligand binding and liquid chromatography–mass spectrometry.

Multi-Specific Antibodies for Cancer Immunotherapy

Abstract: Targeted treatment of cancer with monoclonal antibodies has added to the beneficial outcome of patients. In an attempt to improve anti-tumor activity of monoclonal antibodies, multi-specific antibodies have entered the research arena. To date, only a few multi-specific constructs have entered phase III clinical trials, in contrast to classical monoclonal antibodies, which are the standard first-line therapy in several tumor entities. In this review, we will assess selected multi-specific antibodies in pre-clinical and clinical development that may be new treatment options for cancer patients in the very near future. We will further evaluate therapy modalities including the timely distribution or the combination of various therapeutic approaches and assess the potential role of multi-specific antibodies in cancer treatment.

Antibody–Cytokine Fusion Proteins for Cancer Immunotherapy: An Update on Recent Developments

Abstract: Treatment with cytokines holds great potential for cancer immunotherapy, but is generally restricted by systemic toxicity. Tumor-directed targeting in the form of antibody fusion proteins appears to be an attractive strategy to overcome this problem. In the last twenty years, continuous efforts in developing appropriate molecules have retrieved a variety of antibody fusion proteins that reveal promising therapeutic effects in preclinical studies. Currently, several candidates are in clinical evaluation. Here, recent developments exploring diverse antibody formats, tumor targets and cytokines of different families as well as strategies addressing cytokine modification or presentation are discussed and clinical trials summarized at a glance. Thus, antibody–cytokine fusion proteins are becoming progressively improving immunologic reagents that raise expectations mainly for combinatorial cancer therapies.

Attenuation of Carbon Tetrachloride-Induced Hepatic Injury with Curcumin-Loaded Solid Lipid Nanoparticles

Abstract: Curcumin, an established pleiotropic agent, has potential for hepatoprotection owing to its powerful antioxidant, anti-inflammatory, and antifibrogenic properties. However, its poor bioavailability limits its use in therapeutics. In this study, we aimed to package curcumin into solid lipid nanoparticles (C-SLNs) to improve its bioavailability and compare the efficacy of C-SLNs with that of free curcumin and silymarin, a well-established hepatoprotectant in clinical use, against carbon tetrachloride (CCl4)-induced hepatic injury in rats, post-induction. A self-recovery group to which no treatment was given was also employed for quantifying self-healing of hepatic tissue, if any. C-SLNs (particle size 147.6 nm), prepared using a microemulsification technique, were administered to rats post-treatment with CCl4 (1 ml/kg body weight [BW] twice weekly for 2 weeks, followed by 1.5 ml/kg BW twice weekly for the subsequent 2 weeks). The extent of liver damage and repair in terms of histopathology and levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), oxidative stress markers (malondialdehyde, superoxide dismutase, and reduced glutathione) and a pro-inflammatory response marker, tumor necrosis factor (TNF)-α, were determined in both the CCl4 group and the treatment groups. C-SLNs (12.5 mg/kg) significantly (p < 0.001–0.005) attenuated histopathological changes and oxidative stress, and also decreased induction of ALT, AST, and TNF-α in comparison with free curcumin (100 mg/kg), silymarin (25 mg/kg), and self-recovery groups. Curcumin could be used as a therapeutic agent for hepatic disorders, provided it is loaded into a suitable delivery system.

A comprehensive safety evaluation of trabectedin and drug-drug interactions of trabectedin-based combinations

Abstract: Trabectedin (Yondelis®) is a potent marine-derived antineoplastic drug with high activity against various soft tissue sarcoma (STS) subtypes as monotherapy, and in combination with pegylated liposomal doxorubicin (PLD) for the treatment of patients with relapsed platinum-sensitive ovarian cancer. This article reviews the safety and pharmacokinetic profiles of trabectedin. Records were identified using predefined search criteria using electronic databases (e.g. PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published between 1 January 2006 and 1 April 2014 were included. The current safety and tolerability profile of trabectedin, based on the evaluation in clinical trials of patients treated with the recommended treatment regimens for STS and recurrent ovarian cancer, was reviewed. Trabectedin as monotherapy or in combination with PLD, was not associated with cumulative and/or irreversible toxicities, such as cardiac, pulmonary, renal, or oto-toxicities, often observed with other common chemotherapeutic agents. The most common adverse drug reactions (ADRs) were myelosuppression and transient hepatic transaminase increases that were usually not clinically relevant. However, trabectedin administration should be avoided in patients with severe hepatic impairment. Serious and fatal ADRs were likely to be related to pre-existing conditions. Doxorubicin or PLD, carboplatin, gemcitabine, or paclitaxel when administered before trabectedin, did not seem to influence its pharmacokinetics. Cytochrome P450 (CYP) 3A4 has an important role in the metabolism of trabectedin, suggesting a risk of drug–drug interactions with trabectedin used in combination with other CYP3A4 substrates. Trabectedin has a favorable risk/efficacy profile, even during extended treatment in pretreated patients.

Bosutinib: A Review of Its Use in Patients with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia

Abstract: Bosutinib (Bosulif®) is an orally administered small molecule tyrosine kinase inhibitor (TKI) of BCR–ABL and SRC family kinases. It is indicated for the treatment of adult patients with chronic-, accelerated-, or blast-phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy (imatinib, dasatinib, or nilotinib) [USA] or for a small subpopulation of these patients for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options (EU). In a multinational pivotal trial (n = 547), bosutinib treatment resulted in a major cytogenetic response (MCyR) at 24 weeks in one-third of all treated patients with imatinib-resistant chronic-phase CML who had no previous exposure to any TKIs other than imatinib (primary endpoint), with similar results observed in chronic-phase CML patients who were intolerant of imatinib and naive to all other TKIs. MCyRs were also seen in more than one–quarter of evaluable patients with chronic-phase CML previously treated with multiple TKIs. Most of the patients with chronic-phase CML achieved a complete hematologic response with bosutinib and some patients with advanced phases of CML achieved an overall hematologic response. Responses were seen irrespective of the type of BCR-ABL mutation at baseline, except T315I. Bosutinib had a manageable tolerability profile in the pivotal trial, with ≤21 % of patients with chronic-phase CML discontinuing the treatment because of adverse events. Diarrhea was the most common adverse event but was generally manageable, with only few patients discontinuing the treatment because of diarrhea. Therefore, bosutinib is a useful TKI option for patients with Ph+ CML in second-line or greater settings.

Human immunoglobulin 10 % with recombinant human hyaluronidase: replacement therapy in patients with primary immunodeficiency disorders.

Abstract: Human immunoglobulin is an established replacement therapy for patients with primary immunodeficiency disorders (PIDs). Recombinant human hyaluronidase (rHuPH20) is a spreading factor that temporarily digests hyaluronan in the skin interstitium enabling large volumes of fluid or drug solutions to be infused and absorbed subcutaneously. HyQvia® (IGHy) is a new combination product whereby rHuPH20 is injected subcutaneously, followed by human immunoglobulin 10 % infused through the same needle. Thus, IGHy can be administered at a reduced frequency compared with non-facilitated subcutaneous injection of human immunoglobulin, and with a lower frequency of infusion reactions than with intravenous administration. Home-based administration of IGHy is also feasible for adequately trained patients. IGHy was compared with intravenous human immunoglobulin 10 % in a non-randomized, open-label, phase 3 study in patients aged ≥2 years with PIDs who were receiving human immunoglobulin replacement therapy (n = 87). In this study, trough IgG concentrations, acute serious bacterial infection rates (primary endpoint) and occurrences of adverse events during the IGHy treatment period were generally similar to those observed during an intravenous treatment period. IGHy was associated with a numerically lower rate of systemic adverse events and a numerically higher rate of localized adverse events than those observed with intravenous treatment. Compared with intravenous administration, IGHy was administered at a significantly higher maximum flow rate and at a similar frequency. Most patients preferred IGHy over intravenous administration. IGHy offers a new method for subcutaneous delivery of human immunoglobulin replacement therapy in patients with PIDs.

siRNA technology in kidney transplantation: current status and future potential.

Abstract: Kidney transplantation is one of the most common transplantation operations in the world, accounting for up to 50 % of all transplantation surgeries. To curtail the damage to transplanted organs that is caused by ischemia–reperfusion injury and the recipient’s immune system, small interfering RNA (siRNA) technology is being explored. Importantly, the kidney as a whole is a preferential site for non-specific systemic delivery of siRNA. To date, most attempts at siRNA-based therapy for transplantation-related conditions have remained at the in vitro stage, with only a few of them being advanced into animal models. Hydrodynamic intravenous injection of naked or carrier-bound siRNAs is currently the most common route for delivery of therapeutic constructs. To our knowledge, no systematic screens for siRNA targets most relevant for kidney transplantation have been attempted so far. A majority of researchers have arrived at one or another target of interest by analyzing current literature that dissects pathological processes taking place in transplanted organs. A majority of the genes that make up the list of 53 siRNA targets that have been tested in transplantation-related models so far belong to either apoptosis- or immune rejection-centered networks. There is an opportunity for therapeutic siRNA combinations that may be delivered within the same delivery vector or injected at the same time and, by targeting more than one pathway, or by hitting the same pathways within two different key points, will augment the effects of each other.