Guardians at the gate: Biosimilar and patent reform legislation could fundamentally change the guards for therapeutic monoclonal antibodies—Part 2

Patent protection and FDA exclusivities are the two principal forms of protection available to companies that develop therapeutic monoclonal antibodies. Propo-sed changes to both forms of protection are currently being debated in the United States Congress. Specifically, Congress is presently debating both biosimilar and patent reform legislations. Although no bill has yet passed, it is expected that patent reform legislation should pass this year. It is less likely that a biosimilar bill will pass this year. However, when legislations are enacted, the changes will significantly impact the business of therapeutic monoclonal antibodies.Key words: patent reform, biosimilar legislation, therapeutic antibody, Eshoo, Waxman, S 615, HR 1260     

单克隆抗体仿制药物的结构分析策略

市场高达数千亿美元的单克隆抗体药物即将结束专利保护期,这对发展中国家产业升级,提高国民医疗水平,都是一次难得的战略机遇。然而,单抗类蛋白仿制药的研发与质控工作难度巨大,必须使用液相色谱-质谱联用技术进行分析。针对单抗仿制药结构必须进行的分析项目(氨基酸序列表达正确性、糖基化修饰形态相似性、以及高级结构统一致性)的液质分析方法进行了系统介绍。此外还就分析工作效率及质控过程的法规依从问题予以讨论。     

Guardians at the gate: Patent protection for therapeutic monoclonal antibodies—part 1

Patents provide one of the few protections companies can avail themselves of to help protect their therapeutic monoclonal antibody products. Just as the therapeutic monoclonal antibody field is constantly evolving, so too is the legal environment surrounding these inventions. In a series of articles, the general state of the law surrounding therapeutic antibodies will be explained, and important challenges to this technology area will be discussed. Much is at stake when companies market therapeutic monoclonal antibodies; therefore, a firm understanding of this important form of protection is critically important for anyone developing such products.Key words: patent, therapeutic, monoclonal antibodies, KSR, life cycle management     

Regulatory considerations in oncologic biosimilar drug development

Biosimilar monoclonal antibodies are being developed globally for patients with different types of solid tumors and hematologic malignancies. Applications for proposed biosimilar monoclonal antibodies are being submitted to the regulatory authorities around the world and may increase patient access to key treatment options upon approval. An understanding among stakeholders (e.g., physicians, patients and their caregivers, pharmacists, payers) of the approval criteria, as well as the similarities and differences in regulatory pathways involved in biosimilar approval in different countries, as presented in this review, will facilitate identification of high-quality, safe, monoclonal antibodies that have been developed according to strict, biosimilar regulatory standards. Further guidance and resolution of the ongoing discussions on biosimilar labeling, naming, automatic substitution, and indication extrapolation may ensure, in the future, an effective and appropriate use of biosimilar monoclonal antibodies by oncologists and other stakeholders in daily clinical practice.     

Monoclonal antibodies biosimilarity assessment using transient isotachophoresis capillary zone electrophoresis-tandem mass spectrometry

Out of all categories, monoclonal antibody (mAb) therapeutics attract the most interest due to their strong therapeutic potency and specificity. Six of the 10 top-selling drugs are antibody-based therapeutics that will lose patent protection soon. The European Medicines Agency has pioneered the regulatory framework for approval of biosimilar products and approved the first biosimilar antibodies by the end of 2013. As highly complex glycoproteins with a wide range of micro-variants, mAbs require extensive characterization through multiple analytical methods for structure assessment rendering manufacturing control and biosimilarity studies particularly product and time-consuming. Here, capillary zone electrophoresis coupled to mass spectrometry by a sheathless interface (CESI-MS) was used to characterize marketed reference mAbs and their respective biosimilar candidate simultaneously over different facets of their primary structure. CESI-MS/MS data were compared between approved mAbs and their biosimilar candidates to prove/disconfirm biosimilarity regarding recent regulation directives. Using only a single sample injection of 200 fmol, CESI-MS/MS data enabled 100% amino acids (AA) sequence characterization, which allows a difference of even one AA between 2 samples to be distinguished precisely. Simultaneously glycoforms were characterized regarding their structures and position through fragmentation spectra and glycoforms semiquantitative analysis was established, showing the capacity of the developed methodology to detect up to 16 different glycans. Other posttranslational modifications hotspots were characterized while their relative occurrence levels were estimated and compared to biosimilars. These results proved the value of using CESI-MS because the separation selectivity and ionization efficiency provided by the system allowed substantial improvement in the characterization workflow robustness and accuracy. Biosimilarity assessment could be performed routinely with a single injection of each candidate enabling improvements in the biosimilar development pipeline.     

Monoclonal antibodies biosimilarity assessment using transient isotachophoresis capillary zone electrophoresis-tandem mass spectrometry

Out of all categories, monoclonal antibody (mAb) therapeutics attract the most interest due to their strong therapeutic potency and specificity. Six of the 10 top-selling drugs are antibody-based therapeutics that will lose patent protection soon. The European Medicines Agency has pioneered the regulatory framework for approval of biosimilar products and approved the first biosimilar antibodies by the end of 2013. As highly complex glycoproteins with a wide range of micro-variants, mAbs require extensive characterization through multiple analytical methods for structure assessment rendering manufacturing control and biosimilarity studies particularly product and time-consuming. Here, capillary zone electrophoresis coupled to mass spectrometry by a sheathless interface (CESI-MS) was used to characterize marketed reference mAbs and their respective biosimilar candidate simultaneously over different facets of their primary structure. CESI-MS/MS data were compared between approved mAbs and their biosimilar candidates to prove/disconfirm biosimilarity regarding recent regulation directives. Using only a single sample injection of 200 fmol, CESI-MS/MS data enabled 100% amino acids (AA) sequence characterization, which allows a difference of even one AA between 2 samples to be distinguished precisely. Simultaneously glycoforms were characterized regarding their structures and position through fragmentation spectra and glycoforms semiquantitative analysis was established, showing the capacity of the developed methodology to detect up to 16 different glycans. Other posttranslational modifications hotspots were characterized while their relative occurrence levels were estimated and compared to biosimilars. These results proved the value of using CESI-MS because the separation selectivity and ionization efficiency provided by the system allowed substantial improvement in the characterization workflow robustness and accuracy. Biosimilarity assessment could be performed routinely with a single injection of each candidate enabling improvements in the biosimilar development pipeline.     

Emerging genomic technologies and the concept of personalized medicine: An overview of ethical,legal and social implications

With the completion of the Human Genome Project in May 2006, genetic testing for every American is rapidly becoming a reality. As the advanced technology fuels the path towards personalized medicine, genetic nondiscrimination legislation follows closely behind. It seems that the 2007 Genetic Information Nondiscrimination Act (GINA) will finally pass through both chambers of Congress and will be signed by the President, but questions remain. On May 1, 2008, the House passed GINA by a vote of 414 to 1. Why is this the year that genetic nondiscrimination legislation could finally become the reality? Is this the beginning of a new relationship between science and policy, where policy is finally catching up? We examine the answers to these questions through a look at the history of genetic nondiscrimination legislation and where it stands today, including arguments for and against the bill. We conclude by discussing how we can achieve a future of safe personalized medicine for the populous, which would require continuous productive interactions between policymakers and scientists.     

Guardians at the gate

Patents provide one of the few protections companies can avail themselves of to help protect their therapeutic monoclonal antibody products. Just as the therapeutic monoclonal antibody field is constantly evolving, so too is the legal environment surrounding these inventions. In a series of articles, the general state of the law surrounding therapeutic antibodies will be explained, and important challenges to this technology area will be discussed. Much is at stake when companies market therapeutic monoclonal antibodies; therefore, a firm understanding of this important form of protection is critically important for anyone developing such products.     

Possible Molecular Mechanisms Involved in Nickel,Zinc and Selenium Hyperaccumulation in Plants

Abstract

The recent financial meltdown has muted the patent reform debate in the United States. But given that President Obama, as well as many members of Congress, support patent reform, we expect the debate to resurface. In this essay, we look carefully at reports from three prestigious organizations which have been enormously influential in the debate. We examine the empirical basis contained in these reports upon which proposed legislative changes are based. We conclude that the empirical data being used to justify the need for reform either has serious methodological limitations or is non-existent. Moreover, we review recent court decisions which have already altered the patent environment calling into further question whether the limited data that exists is still applicable. The effect of these recent decisions has not been adequately evaluated or assessed. Thus, we recommend other empirical studies are needed to inform public policy as to whether patent reform is necessary.     

The challenge of indication extrapolation for infliximab biosimilars

A biosimilar is intended to be highly similar to a reference biologic such that any differences in quality attributes (i.e., molecular characteristics) do not affect safety or efficacy. Achieving this benchmark for biologics, especially large glycoproteins such as monoclonal antibodies, is challenging given their complex structure and manufacturing. Regulatory guidance on biosimilars issued by the U.S. Food and Drug Administration, Health Canada and European Medicines Agency indicates that, in addition to a demonstration of a high degree of similarity in quality attributes, a reduced number of nonclinical and clinical comparative studies can be sufficient for approval. Following a tiered approach, clinical studies are required to address concerns about possible clinically significant differences that remain after laboratory and nonclinical evaluations. Consequently, a critical question arises: can clinical studies that satisfy concerns regarding safety and efficacy in one condition support “indication extrapolation” to other conditions? This question will be addressed by reviewing the case of a biosimilar to infliximab that was approved recently in South Korea, Europe, and Canada for multiple indications through extrapolation. The principles discussed should also apply to biosimilars of other monoclonal antibodies that are approved to treat multiple distinct conditions.     

Correct primary structure assessment and extensive glyco-profiling of cetuximab by a combination of intact,middle-up,middle-down and bottom-up ESI and MALDI mass spectrometry techniques

The European Medicines Agency received recently the first marketing authorization application for a biosimilar monoclonal antibody (mAb) and adopted the final guidelines on biosimilar mAbs and Fc-fusion proteins. The agency requires high similarity between biosimilar and reference products for approval. Specifically, the amino acid sequences must be identical. The glycosylation pattern of the antibody is also often considered to be a very important quality attribute due to its strong effect on quality, safety, immunogenicity, pharmacokinetics and potency. Here, we describe a case study of cetuximab, which has been marketed since 2004. Biosimilar versions of the product are now in the pipelines of numerous therapeutic antibody biosimilar developers. We applied a combination of intact, middle-down, middle-up and bottom-up electrospray ionization and matrix assisted laser desorption ionization mass spectrometry techniques to characterize the amino acid sequence and major post-translational modifications of the marketed cetuximab product, with special emphasis on glycosylation. Our results revealed a sequence error in the reported sequence of the light chain in databases and in publications, thus highlighting the potency of mass spectrometry to establish correct antibody sequences. We were also able to achieve a comprehensive identification of cetuximab’s glycoforms and glycosylation profile assessment on both Fab and Fc domains. Taken together, the reported approaches and data form a solid framework for the comparability of antibodies and their biosimilar candidates that could be further applied to routine structural assessments of these and other antibody-based products.     

The future of monoclonal antibody technology

With the rapid growth of monoclonal antibody-based products, new technologies have emerged for creating modified forms of antibodies, including fragments, conjugates and multi-specific antibodies. We created a database of 450 therapeutic antibodies in development to determine which technologies and indications will constitute the “next generation” of antibody products. We conclude that the antibodies of the future will closely resemble the antibodies that have already been approved for commercial sale.Key words: monoclonal antibody, therapeutic products, bispecific antibodies, antibody conjugates     

9th Annual European Antibody Congress,November 11–13, 2013, Geneva,Switzerland

The annual European Antibody Congress (EAC) has traditionally been the key event for updates on critical scientific advances in the antibody field, and 2013 was no exception. Organized by Terrapinn, the well-attended meeting featured presentations on considerations for developing antibodies and antibody-like therapeutics, with separate tracks for antibody-drug conjugates, naked antibodies, and multispecific antibodies or protein scaffolds. The overall focus of the EAC was current approaches to enhance the functionality of therapeutic antibodies or other targeted proteins, with the ultimate goal being improvement of the safety and efficacy of the molecules as treatments for cancer, immune-mediated disorders and other diseases. Roundtable discussion sessions gave participants opportunities to engage in group discussions with industry leaders from companies such as Genmab, Glenmark Pharmaceuticals, MedImmune, Merrimack Pharmaceuticals, and Pierre Fabre. As the 2013 EAC was co-located with the World Biosimilar Congress, participants also received an update on European Medicines Agency guidelines and thoughts on the future direction and development of biosimilar antibodies in the European Union.     

7th Annual European Antibody Congress 2011: November 29–December 1, 2011, Geneva,Switzerland

The 7^th European Antibody Congress (EAC), organized by Terrapin Ltd., was again held in Geneva, Switzerland, following on the tradition established with the 4^th EAC. The 2011 version of the EAC was attended by nearly 250 delegates who learned of the latest advances and trends in the global development of antibody-based therapeutics. The first day focused on advances in understanding structure-function relationships, choosing the best format, glycoengineering biobetter antibodies, improving the efficacy and drugability of mAbs and epitope mapping. On the second day, the discovery of novel targets for mAb therapy, clinical pipeline updates, use of antibody combinations to address resistance, generation and identification of mAbs against new targets and biosimilar mAb development were discussed. Antibody-drug conjugates, domain antibodies and new scaffolds and bispecific antibodies were the topics of the third day. In total, nearly 50 speakers provided updates of programs related to antibody research and development on-going in the academic, government and commercial sectors.Key words: therapeutic antibodies, antibody-drug conjugates, protein scaffolds, bispecific antibodies, biosimilar antibodies     

Expression of recombinant human mutant granulocyte colony stimulating factor (Nartograstim) in Escherichia coli

The human granulocyte colony stimulating factor (hG-CSF) plays an important role in hematopoietic cell proliferation/differentiation and has been widely used as a therapeutic agent for treating neutropenias. Nartograstim is a commercial G-CSF that presents amino acid changes in specific positions when compared to the wild-type form, which potentially increase its activity and stability. The aim of this work was to develop an expression system in Escherichia coli that leads to the production of large amounts of a recombinant hG-CSF (rhG-CSF) biosimilar to Nartograstim. The nucleotide sequence of hg-csf was codon-optimized for expression in E. coli. As a result, high yields of the recombinant protein were obtained with adequate purity, structural integrity and biological activity. This protein has also been successfully used for the production of specific polyclonal antibodies in mice, which could be used in the control of the expression and purification in an industrial production process of this recombinant protein. These results will allow the planning of large-scale production of this mutant version of hG-CSF (Nartograstim), as a potential new biosimilar in the market.     

美国国家生物工程食品信息披露标准法案评析

美国“国家生物工程食品信息披露标准”法案出台的主要目的是统一转基因食品标识立法,避免出现州各自为政、部分州与联邦对立的局面,减少州际食品生产和交易的成本。法案优先于州标识立法,它在要求“强制”的同时,也为经营者提供了多种信息披露方式。披露要求及标准则由农业部在两年内制定规章予以确定。这一法案是美国各方妥协的结果,并未影响原有的生物技术政策和管理原则。在我国,转基因技术相关立法上亦存在矛盾和冲突,转基因食品标识问题尚未有定论。美国立法妥协的艺术值得我国借鉴,各方应当认可国家发展生物技术的目标。我国转基因食品标识立法需要高层次立法的明确授权,设置更多样的标识方式,并进行充分的法律实施评估。     

The future of monoclonal antibody technology

With the rapid growth of monoclonal antibody-based products, new technologies have emerged for creating modified forms of antibodies, including fragments, conjugates and multi-specific antibodies. We created a database of 450 therapeutic antibodies in development to determine which technologies and indications will constitute the “next generation” of antibody products. We conclude that the antibodies of the future will closely resemble the antibodies that have already been approved for commercial sale.     

全球PD-1/PD-L1单克隆抗体市场竞争格局

目的:从产品开发角度分析PD-1/PD-L1单克隆抗体的发展现状和未来趋势。方法:检索科睿唯安(Clarivate Analytics)的Cortellis数据库的数据,利用定量分析法和对比分析法对检索结果进行分析。结果:目前已有5种PD-1/PD-L1单克隆抗体上市、4种PD-1/PD-L1单克隆抗体处于预注册及6种PD-1/PD-L1单克隆抗体处于临床Ⅲ期,未来市场上的PD-1/PD-L1单克隆抗体将呈现快速增长趋势。此外,PD-1/PD-L1单克隆抗体的商业交易也越来越多,目前共发生包括药物开发及商业化许可、专利资产出售及早期药物研发合作等10余起交易,其中药物开发及商业化许可是最主要的交易模式。结论:虽然PD-1/PD-L1单克隆抗体市场尚处于起步阶段,但随着未来技术的不断发展改进,相信未来有更多的PD-1/PD-L1单克隆抗体上市,为癌症及其他疾病的治疗提供新的契机。     

Worldwide experience with biosimilar development

Limited access for high-quality biologics due to cost of treatment constitutes an unmet medical need in the United States (US) and other regions of the world. The term “biosimilar” is used to designate a follow-on biologic that meets extremely high standards for comparability or similarity to the originator biologic drug that is approved for use in the same indications. Use of biosimilar products has already decreased the cost of treatment in many regions of the world, and now a regulatory pathway for approval of these products has been established in the US. The Food and Drug Administration (FDA) led the world with the regulatory concept of comparability, and the European Medicines Agency (EMA) was the first to apply this to biosimilars. Patents on the more complex biologics, especially monoclonal antibodies, are now beginning to expire and biosimilar versions of these important medicines are in development. The new Biologics Price Competition and Innovation Act allows the FDA to approve biosimilars, but it also allows the FDA to lead on the formal designation of interchangeability of biosimilars with their reference products. The FDA’s approval of biosimilars is critical to facilitating patient access to high-quality biologic medicines, and will allow society to afford the truly innovative molecules currently in the global biopharmaceutical industry’s pipeline.     

Worldwide experience with biosimilar development

Limited access for high-quality biologics due to cost of treatment constitutes an unmet medical need in the US and other regions of the world. The term “biosimilar” is used to designate a follow-on biologic that meets extremely high standards for comparability or similarity to the originator biologic drug that is approved for use in the same indications. Use of biosimilar products has already decreased the cost of treatment in many regions of the world and now a regulatory pathway for approval of these products has been established in the US. The Food and Drug Administration (FDA) led the world with the regulatory concept of comparability and the European Medicines Agency (EMA) was the first to apply this to biosimilars. Patents on the more complex biologics, especially monoclonal antibodies, are now beginning to expire and biosimilar versions of these important medicines are in development. The new Biologics Price Competition and Innovation Act (BPCIA) allows the FDA to approve biosimilars and allows the FDA to lead on the formal designation of interchangeability of biosimilars with their reference products. The FDA''s approval of biosimilars is critical to facilitating patient access to high-quality biologic medicines and will allow society to afford the truly innovative molecules currently in the global biopharmaceutical industry''s pipeline.Key words: monoclonal antibodies (mAbs), biosimilars, recombinant biopharmaceuticals