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Oligonucleotide (OGN) therapy is increasingly recognized as an important therapeutic modality on the promise of curing diseases. However, unlike most biotherapeutics, the development of OGN drugs often requires their determination with high sensitivity and specificity in multiple and complex biologic matrices such as blood and tissues in order to measure their exposure and distribution for understating PK, PD and safety.
At Frontage Laboratories, we have developed highly sensitive and specific quantitative methods for determination of OGN in plasma and tissues using hybridization immunoassay and LC-MS techniques. In this webinar, we will present the method development, validation and the comparison of these techniques for the quantification of OGN as well as a case study with antisense oligonucleotides.
Overcoming the Challenges in Bioanalysis of Oligonucleotide-based Therapies and Relevance to the Clinical Development Plan
“Gene therapy provides the hope of actual cures. These therapies still have many challenges to overcome before they will become widely developed therapeutic options.” Featuring Frontage's Chief Business Officer, Hugh Davis, and Vice President of Biologics Services, Weiping Shao
Bioanalysis Zone podcast featuring Hugh Davis, PhD discussing Gene Therapy
Download ResourceWhen the Cell is the Drug: Cell and Gene Therapy Panel Discussion featuring Frontage Laboratories expert and Vice President of Biologics Services, Dr. Weiping Shao.
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Over the years, the pharmaceutical industry has made steady progress in improving the safety of drugs in development. Consequently, in 2015, only 14 percent of Phase III studies failed due to safety (compared to 55 percent for efficacy), down from 21 percent in 2013. In other words, “efforts to remove unsafe agents earlier in the development cycle are paying off.” Much of this success in small molecules relates to careful and methodical work done well before the Investigational New Drug (IND) application.
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The biological activity of biopharmaceutical compounds (such as peptides, monoclonal antibodies, growth factors, and cytokines) has a direct bearing on their potency, which is a critical quality
attribute and a representation of efficacy. For biopharma companies,
measuring a cell’s bioactivity is important when:
• Screening compounds to develop the lead candidate;
• Validating potency when applying for regulatory approval;
• Confirming that the biological characteristics of the productremain consistent throughout the development cycle andfrom lot-to-lot, or site-to-site;
• Controlling for a compound’s quality prior to productrelease (either for a clinical trial or commercialization);
• Testing for stability; and
• Demonstrating biosimilarity between a biosimilar and theoriginator compound.
Stability testing is, in essence, a quality control process and is therefore a vital component of every phase of clinical development for both large and small molecules – from early phase through to and including post approval. It should be treated as an ongoing program rather than as a periodic exercise.
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Most of the advanced instruments used in bioanalysis—such as Gas Chromatography (GC), High Performance Liquid Chromatography (HPLC), and Liquid Chromatography-Mass Spectrometry (LC-MS) for example—are automated. Thus, they are controlled by complex computer systems, and the information they generate is stored electronically. If these systems are to be used in regulated research studies in the US, EU, and Japan, the instruments themselves must be qualified and their supporting software and processes must be validated as meeting regulatory requirements.
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Monoclonal antibodies and next generation molecules such as antibody-drug conjugates (ADC) are being developed and moved into early phase clinical testing. These new molecules bring challenges for measuring immunogenicity within human serum samples.
Challenges:
• Therapeutic monoclonal antibodies could have structural regions which could contain ADA binding domains [Figure 1].
• ADC molecule has a mAb joined to a small drug by a linker region [Figure 2]. This may lead to a highly potent drug which is also a selective binder of a specific tumor antigen; however, the structure may also present a neoepitope to the immune system.
• Development of anti-drug antibody (ADA) assays to both mAb’s and ADC’s very commonly has demonstrated the presence of pre-existing antibodies (PEXA) in a small percentage of drug naïve normal human serum samples. It is currently unclear as to the evolutionary mechanism that has allowed PEXA to develop. Their presence may serve as a regulatory mechanism to suppress the immune system under certain conditions.
Approach:
• Regardless of how pre-existing antibodies may have developed, measuring an anti-drug antibody (ADA) response in serum samples may present additional challenges with these pre-existing molecules present. Here, we outline a strategy to determine where on the molecule the ADA reactivity is directed against.
Antibody drug conjugates (ADCs) has become promising therapy for the treatment of cancers. Among all the ADCs under developing, 2/3 of them are interchain cysteine linked ADCs. The ADCs are manufactured by partially reduce the 4 pairs of interchain disulfide bond followed by conjugate cytotoxic payloads to the thiols, as a consequence, the antibodies are linked with 0, 2, 4, 6, 8 drugs. The drug to antibody ratio (DAR) and the drug linking position are important parameters that affect the therapeutic effects and need to be well characterized.
Sample preparation:
The ADCs in the mouse plasma were purified by affinity capture with anti-human IgG beads followed wash with PBS supplied with 0.1% tween-20. The ADC was eluted with 0.1% TFA and neutralized with 1M tris (PH=8).
Challenges:
1. Heavy chain positional isomers separation and Identification.
2. Heavy chain positional isomers abundance determination.
Methods:
1. Reduced ADC HRMS analysis. The Purified ADC was deglycosylated and reduced and then analyzed with HRMS.
2. Bottom up analysis. Purified ADC was treated with IdeS to remove Fc part followed by denaturation, reduction, alkylation, chymotrpsin digestion and then subject to LC/MS analysis.
3. LC-MS/MS analysis. Isomer fraction were collected and digested with trypsin, the digest was analyzed by LC/MS/MS for drug linking position identification.
In this study, we developed and validated a LC-MS/MS method for the determination of Fluticasone propionate and Fluticasone 17β-carboxylic acid propionate (Fluticasone metabolite) in human K3EDTA plasma using Fluticasone propionate-d5 and Fluticasone 17β-carboxylic acid propionate-d3 as the internal standards (IS) using positive and negative TIS switch during analysis
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Frontage Laboratories, Inc. is a CRO providing integrated, scientifically-driven research, analytical and development services. With over 17 years of experience, we have successfully assisted our clients in advancing hundreds of compounds through the drug development process.
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We are a CRO providing integrated, scientifically-driven research, analytical and development services throughout the drug discovery and development process to enable biopharmaceutical companies to achieve their drug development goals. We have enabled many innovator, generic and consumer health companies of all sizes to file IND, NDA, ANDA, BLA and 505(b)(2) submissions in global markets allowing for successful development of important therapies and products for patients. We are committed to providing rigorous scientific expertise to ensure the highest quality and compliance. We have successfully assisted clients to advance hundreds of molecules through development to commercial launch in global markets.
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With over 20 years of experience in execution of comprehensive Phase I-IIa studies, Frontage Clinical Services has full capabilities to conduct a broad range of study types (e.g. PK, confinement and ambulatory) in support of tobacco related studies. With extensive expertise in a wide variety of delivery systems, we are well-positioned to conduct tobacco-focused clinical research studies.
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Frontage Laboratories provides extensive support to clients in the Agrochemicals industry. Our broad service offering includes biological, chemical, and regulatory support in a GLP-compliant facility.
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Frontage’s Bioanalytical Team is highly experienced in developing, qualifying and validating Biomarker assays. We have expertise in ELISA, ECL based platforms as well as ultra-sensitive detection capabilities (Quanterix SimoaTM) for quantitation in the femtogram/mL range including single and multiplex analysis in various disease categories (e.g. Inflammation, Oncology, Neuroscience, Infectious Diseases, Respiratory, etc.).
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Gain access to comprehensive biologics services in support of advanced development programs with Frontage’s bioanalytical laboratory. We have the capabilities to analyze virtually any peptide, protein or antibody, and have built a reputation for solving technical challenges related to assay development and validation.
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Frontage Laboratories provides bioanalytical services to help support your full drug development. Our state-of-the-art equipment and experienced personnel will quickly and efficiently provide you with the data to support your programs. We provide the resources of a highly skilled, client- focused staff with extensive academic, scientific and pharmaceutical industry experience.
Download Resource Frontage’s experienced staff and state-of-the-art instrumentation delivers data you can trust. Count on Frontage Laboratories for reliability. From method development or transfer and validation to sample analysis and reporting, Frontage’s bioanalytical team has earned a reputation for consistent and high-quality delivery, project after project. Our bioanalytical expertise extends to combined small and large molecules such as protein, antibody, antibody drug conjugates as well as biomarker analysis for small molecule drug candidates.
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Frontage’s clinical teams have set new standards for rapid start-up and efficient study conduct. Our experienced staff provides study management services for all phases of clinical research, including study design, protocol and ICF development, IRB submission, study execution, data management, pharmacokinetic/pharmacodynamic analysis, programming, biostatistics, and medical writing, to take each study from start to finish.
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For early phase clinical trial materials, choose a product development team focused on scalability and performance. Ensure comprehensive product analysis with Frontage’s team of experienced analytical scientists.
Frontage brings
Biologics or biopharmaceuticals are inherently more complex than small-molecule drugs. You need the right team to help you. Frontage has expertise and state of the art instrumentation necessary for the analytical method development, validation and transfer for complex biopharmaceutical compounds. Using bottom up, middle up/down, and top down approaches, we offer analytical support for characterization of primary, secondary and tertiary structures, post translational modifications such as glycosylation, disulfide linkage, antibody drug conjugation, or PEGylation.
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Ensure comprehensive product analysis with Frontage’s team of experienced analytical scientists. We specialize in analytical method development, validation and transfer for product development and clinical trial materials (CTM) manufacturing support, as well as commercial product release and stability testing. Our services are designed to help sponsors throughout the drug development process in their effort to fully characterize drug substances, developmental formulations and commercial drug products.
Download Resource Frontage’s CMC portfolio of services spans drug product development, analysis, delivery and supply, from proof-of-concept, preclinical stages through Phase III clinical trials and commercialization support. With proven success in developing drug products for novel, generic and consumer products, we focus our efforts on clients’ specific needs. Our formulation development experience and capabilities cover a wide range of dosage forms at IND, NDA, ANDA and 505(b)(2) project stages and applications.
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DMPK studies can provide critical data during discovery and development of pharmaceutical and agrochemical products. Frontage’s DMPK services, performed in accredited facilities, can help support lead drug candidate or chemical selection, or help you meet specific regulatory requirements.
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Frontage Laboratories provides drug safety services to guide new therapies from discovery to full development support. Our extensive profile of IND enabling pivotal studies support swift progression of your lead compounds into the clinic – streamlining your development process. We provide the resources of a highly skilled, client-focused staff with extensive academic, scientific and pharmaceutical industry experience.
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