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Advanced Drug Delivery Reviews (v.58, #5-6)
Therapeutic antibodies — Delivering the promise? by Geoff Hale (pp. 633-639).
For more than a century, therapeutic antibodies held the promise of providing specific cures for a wide range of diseases. It was not till the monoclonal era that the difficulties with purity and reproducibility were surmounted. But many obstacles still remained, and it has been a complex process to identify the best specificities, optimise effector functions and avoid unwanted immunogenicity. The academic community made substantial contributions, but higher regulatory hurdles will make this less significant in the future. Optimal delivery to the site of action remains one of the most important issues to be addressed. Monoclonal antibodies are already a significant part of the pharmaceutical market but there is a considerable potential still to be tapped.
Keywords: Therapeutic monoclonal antibodies
Engineering of therapeutic antibodies to minimize immunogenicity and optimize function by Leonard G. Presta (pp. 640-656).
One of the first difficulties in developing monoclonal antibody therapeutics was the recognition that human anti-mouse antibody (HAMA) response limited the administration of murine antibodies. Creative science has lead to a number of ways to counter the immunogenicity of non-human antibodies, primarily through chimeric, humanized, de-immunized, and most recently, human-sequence therapeutic antibodies. Once therapeutic antibodies of low or no immunogenicity were available, the creativity then turned to engineering both the antigen-binding domains (e.g., affinity maturation, stability) and altering the effector functions (e.g. antibody-dependent cellular cytotoxicity, complement-dependent cellular cytotoxicity, and clearance rate).
Keywords: Fc receptor; Effector function; Humanization; FcRn
Latest technologies for the enhancement of antibody affinity by Kim L. Wark; Peter J. Hudson (pp. 657-670).
High affinity antibodies are crucial both for the discovery and validation of biomarkers for human health and disease and as clinical diagnostic and therapeutic reagents. This review describes some of the latest technologies for the design, mutation and selection of high affinity antibodies that provide a paradigm for molecular evolution of a far wider range of proteins including enzymes. Strategies include both in vivo and in vitro methods and embrace the latest concepts for antibody display and selection. Specifically, affinity enhancement can be tailored to the target-binding surface, typically the complementary determining region (CDR) loops in antibodies, whereas enhanced stability, expression or catalytic properties can be affected by selected changes to the core protein scaffold. Together, these technologies provide a rapid and powerful strategy to drive the next generation of protein-based reagents for numerous clinical, environmental and agribusiness applications.
Keywords: Antibody; Affinity; Evolution; In vitro; mutagenesis; In vivo; mutagenesis
Antibody production by John R. Birch; Andrew J. Racher (pp. 671-685).
The clinical and commercial success of monoclonal antibodies has led to the need for very large-scale production in mammalian cell culture. This has resulted in rapid expansion of global manufacturing capacity [1], an increase in size of reactors (up to 20,000Â L) and a greatly increased effort to improve process efficiency with concomitant manufacturing cost reduction. This has been particularly successful in the upstream part of the process where productivity of cell cultures has improved 100Â fold in the last 15Â years. This success has resulted from improvements in expression technology and from process optimisation, especially the development of fed-batch cultures. In addition to improving process/cost efficiencies, a second key area has been reducing the time taken to develop processes and produce the first material required for clinical testing and proof-of-principle. Cell line creation is often the slowest step in this stage of process development. This article will review the technologies currently used to make monoclonal antibodies with particular emphasis on mammalian cell culture. Likely future trends are also discussed.
Keywords: Fed-batch culture; CHO; NS0; Gene expression systems; Downstream processing; Fermentation; Cell line selection
Formulation and delivery issues for monoclonal antibody therapeutics by Ann L. Daugherty; Randall J. Mrsny (pp. 686-706).
Antibodies can have exquisite specificity of target recognition and thus generate highly selective outcomes following their systemic administration. While antibodies can have high specificity, the doses required to treat patients, particularly for a chronic condition, are typically large. Fortunately, advances in production and purification capacities have allowed for the exceptionally large amounts of highly purified monoclonal antibodies to be produced. Additionally, genetic engineering of antibodies has provided a stable of antibody-like proteins that can be easier to prepare. Together, these advances have made antibody-based therapies one of the most commonly pursued pharmaceuticals in biotechnology pipelines. With this success, however, has come a series of technical challenges in the formulation of antibody-based materials to maintain sufficient stability in a variety of configurations and sometimes at particularly high concentrations. This review focuses on issues related to identifying and verifying stable antibody-based formulations.
Keywords: Antibody; Stability; Delivery; Formulation
Current and future issues in the manufacturing and development of monoclonal antibodies by Steven Kozlowski; Patrick Swann (pp. 707-722).
Despite a slow beginning, monoclonal antibodies have had many successes over the past decade. It is important that these successes continue, bringing more products for more indications to market. Although manufacturing is not the most common cause of product failure, product quality issues can delay antibody development. Manufacturing has depended on the triad of process validation, process control and product testing. Applying product knowledge proactively to manufacturing (quality by design) may allow greater flexibility and maintain or improve product quality. An integrated approach to biological characterization is an important aspect of product knowledge. Greater product knowledge also facilitates development in other disciplines. Independent of manufacturing strategy, there are a number of regulatory hurdles in initial and ongoing antibody development. These are described to help prevent unnecessary delays.
Keywords: Monoclonal antibodies; Manufacturing; Product testing; Biological characterization; Quality by design
Application and potential limitations of animal models utilized in the development of trastuzumab (Herceptin®): A case study by Mark Pegram; Debbie Ngo (pp. 723-734).
The preclinical and clinical development of trastuzumab, a humanized monoclonal antibody directed against a juxtamembrane epitope in the HER2 receptor ectodomain, relied heavily on the use of animal models to validate HER2 as a potential MAb target. The identification of HER2 ( neu) as a proto-oncogene was first established in a carcinogen-induced brain tumor in the rat. Transgenic mouse technology led to an understanding of the role of HER2 in pathogenesis of breast cancer. Transfection studies of human HER2 cDNA into murine xenograft models further explored the role HER2 plays in tumor progression and metastasis. A murine subrenal capsule fresh human tumor explant assay was utilized to test efficacy of various murine monoclonal anti-HER2 antibodies, and the data were helpful in choosing the most efficacious for subsequent human engineering for clinical use. HER2-overexpressing xenograft models in athymic mice were used to test the efficacy of anti-HER2 antibodies, develop dose–response relationships, measure drug interactions between trastuzumab and chemotherapy, and optimize dosing schedules of chemotherapeutics combined with trastuzumab. In this work, we will highlight the utility of animal models exploited in the development of trastuzumab – noting not only their contribution to drug development but also their limitations in translation of preclinical data into the clinic. It is likely that the experience we gained in the case of preclinical animal models to study in vivo effects of trastuzumab have parallels in the development of other monoclonal antibodies since overcoming the species boundaries (i.e. cross-reactivity with antigenic determinant, development of cross-species neutralizing antibodies, and cross-species interaction with activating Fc receptors on immune effector cells) are major limitations in the design and interpretation of preclinical/translational experiments designed to fulfill various regulatory requirements prior to initiation of phase I human clinical trials.
Keywords: Therapeutic monoclonal antibodies; Herceptin; Trastuzumab; Preclinical animal models; Breast cancer; HER2(; neu; )
Antibodies for angiogenesis inhibition, vascular targeting and endothelial cell transcytosis by Eveline Trachsel; Dario Neri (pp. 735-754).
The endothelium is increasingly recognized as a target for biomedical intervention, not only for its accessibility to molecular agents coming from the blood-stream, but also for the active role played by endothelial cell proliferation to support diseases such as cancer, blinding ocular disorders and chronic inflammatory conditions. The notion that solid tumors cannot grow beyond a size of few millimeters without inducing the proliferation of new blood vessels has stimulated the search for mediators of angiogenesis and for inhibitors of this process, culminating in the approval of a humanized monoclonal antibody to VEGF-A for oncology applications. In parallel, researchers have begun to consider imaging and therapeutic strategies based on the selective delivery of bioactive agents to the new blood vessels, mediated by monoclonal antibody derivatives. Recently, the field of vascular targeting research has been extended to the investigation of molecular agents that may mediate endothelial cell transcytosis, in the hope to overcome this body barrier for drug delivery. This article reviews some of the most significant advances in these areas, and outlines future challenges and opportunities.
Keywords: Antibodies; Cancer; Angiogenesis; Vascular targeting; Transcytosis
Natural IgM antibodies: The orphaned molecules in immune surveillance by H. Peter Vollmers; Stephanie Brändlein (pp. 755-765).
Natural IgM antibodies are typical victims of prejudices which originated in the mid 80 s. Over the years, these molecules were considered as the pariahs among the immune competent molecules and their characteristic properties, like low affinity, cross-reactivity and pentameric structure, were assessed as useless, difficult, nebulous, etc. Today, mainly based on a few scientists' persistent work and the key discoveries on innate immune recognition, natural IgM antibodies are “back on stage�. Their role in the immune response against bacteria, viruses, fungi and possibly modified self-components as well as in therapy and diagnosis of malignancies is accepted. All the so far negatively judged features are seen in a different light, e.g. low affinity seems to be good for function and does not exclude specificity, and cross-reactivity is no longer judged as unspecific, but instead as a very economic way of immune recognition. And at last, with the use of natural IgM antibodies, a new field of tumor-specific targets has been encountered, the carbo-neo-epitopes. Therefore, by having learned from nature, the renaissance of natural IgM antibodies opens a new area of cancer therapeutics and diagnostics.
Keywords: Natural IgM antibodies; Human antibodies; Immune surveillance; Malignancy