Nanocarriers as an Emerging Platform for Cancer Therapy
Lajos P. Balogh in Nano-Enabled Medical Applications, 2020
Targeting cancer with a mAb was described by Milstein in 1981 [23]. Over the past two decades, the feasibility of antibody-based tissue targeting has been clinically demonstrated (reviewed in refs. [24, 25] with 17 different mAbs approved by the US Food and Drug Administration (FDA) [26]. The mAb rituximab (Rituxan) was approved in 1997 for treatment of patients with non-Hodgkin’s lymphoma—a type of cancer that originates in lymphocytes [27]. A year later, Trastuzumab (Herceptin), an anti-HER2 mAb that binds to ErbB2 receptors, was approved for the treatment of breast cancer [28]. The first angiogenesis inhibitor for treating colorectal cancer, Bevacizumab (Avastin), an anti-VEGF mAb that inhibits the factor responsible for the growth of new blood vessels, was approved in 2004 [29]. Today, over 200 delivery systems based on antibodies or their fragments are in preclinical and clinical trials [16, 30]. Recent developments in the field of antibody engineering have resulted in the production of antibodies that contain animal and human origins such chimeric mAbs, humanized mAbs (those with a greater human contribution), and antibody fragments.
Potential of Antibody Therapy for Respiratory Virus Infections
Sunit K. Singh in Human Respiratory Viral Infections, 2014
The continual burden of disease caused by current and emerging respiratory viruses provides the impetus for research into novel therapeutic options. Much interest has been placed on antibody approaches due to their natural role in the immune response and their high target specificity. In addition, technological advances now permit the development of mAbs against virtually any antigen and the overall functionality may be improved through antibody engineering techniques. Many potently neutralizing mAbs have been generated against clinically important respiratory viruses and an impressive amount of preclinical data exists for many of these mAbs. Elaborate screening techniques have also been described for the generation of fully human heterosubtypic mAbs. The possibility of these “universal” mAbs against emerging respiratory viruses has garnered much interest in the use of mAbs for pandemic preparedness.
The Evolution of MAbs from Research Reagents to Mainstream Commercial Therapeutics
Maurizio Zanetti, J. Donald Capra in The Antibodies, 1999
The development and refinement of antibody engineering techniques has driven the shift in the types of MAbs used in clinical trials represented by the evolution from murine to chimeric to humanized. Eventually, human antibody technology will be advanced and reproducible enough to allow development of totally human antibodies. These should be available in the next few years. In the meantime, one of the ways in which IDEC has attempted to derive antibodies containing a smaller proportion of murine sequences is the development of PRIMATIZED® antibodies. Chimeric, humanized, and PRIMATIZED® antibodies are all currently undergoing evaluation in clinical trials that will finally answer the question of the immunogenicity of these agents. The evolution of antibody technology and its uses are summarized in Figure 2.
Monte Carlo Thompson sampling-guided design for antibody engineering
Published in mAbs, 2023
Taro Kakuzaki, Hikaru Koga, Shuuki Takizawa, Shoichi Metsugi, Hirotake Shiraiwa, Zenjiro Sampei, Kenji Yoshida, Hiroyuki Tsunoda, Reiji Teramoto
Antibody engineering is a modification technology applied to therapeutic antibodies to improve their efficacy, safety, and convenience for patients and caregivers. Recently, antibodies with higher functionality, such as pH-dependent antigen-binding antibodies, have been actively developed.1–4 To acquire the desired activity and pharmaceutical characteristics, a comprehensive mutagenesis approach was implemented, followed by extensive combinations of effective amino acid substitutions.3,4 However, because the number of possible combinations is usually large, it is unfeasible to experimentally evaluate all mutation combinations. Therefore, it would be extremely valuable if more efficient antibody engineering could be achieved using computational methods such as machine learning (ML). In this study, we investigated the optimization of pH-dependent antigen binding of an antibody using Bayesian optimization (BO) as an example of engineering highly functional antibodies.
Comprehensive engineering of a therapeutic neutralizing antibody targeting SARS-CoV-2 spike protein to neutralize escape variants
Published in mAbs, 2022
Taichi Kuramochi, Siok Wan Gan, Adrian W.S. Ho, Bei Wang, Nagisa Kageji, Takeru Nambu, Sayaka Iida, Momoko Okuda-Miura, Wei Shan Chia, Chiew Ying Yeo, Dan Chen, Wen-Hsin Lee, Eve Zi Xian Ngoh, Siti Nazihah Mohd Salleh, Cheng-I Wang, Tomoyuki Igawa, Hideaki Shimada
By comprehensively engineering the antibody, we not only rescued its neutralizing efficacy against escape mutants but simultaneously optimized the antibody to attain drug-like characteristics. This methodology preserved the inherent epitope of the parent antibody while screening for the stringent physicochemical properties that are required for large-scale manufacturing and therapeutic use. By this process, 5A6 was engineered into the final candidate 5A6CCS1, which was significantly improved in terms of escape variant neutralization, physicochemical properties, and pharmacokinetics. 5A6CCS1 exhibited a long half-life in human FcRn transgenic mice and cynomolgus monkeys, and showed good manufacturability. Furthermore, it can be formulated at a high concentration for subcutaneous injection, which is better for making medical treatment more accessible during this pandemic. These data highlight how antibody engineering can be effectively used to improve existing antibody drugs so that they neutralize the emerging escape mutants, bypassing the tedious and repetitive process of re-screening for neutralizing antibodies.
Heparin chromatography as an in vitro predictor for antibody clearance rate through pinocytosis
Published in mAbs, 2020
Thomas E. Kraft, Wolfgang F. Richter, Thomas Emrich, Alexander Knaupp, Michaela Schuster, Andreas Wolfert, Hubert Kettenberger
Monoclonal antibodies (mAbs) represent an important class of therapeutics used in a wide variety of diseases.1 Advanced antibody engineering techniques allow not only humanization and potency optimization, but also the creation of next-generation biotherapeutics such as antibody-drug conjugates, as well as bi- and multi-specific antibodies. This expands the target space and mechanisms of action of the molecules, yielding therapeutic proteins with enhanced functionality. The most prevalent isotype of therapeutic antibody is immunoglobulin G (IgG). A striking feature of IgGs is their comparatively long in vivo half-live (about 23 days), which often allows long dose intervals. Long half-live is the result of IgGs binding to the neonatal Fc receptor (FcRn), which efficiently, albeit not perfectly, protects antibodies from lysosomal degradation. If target-mediated clearance (or target-mediated drug disposition, TMDD) can be neglected, antibodies are generally eliminated through pinocytotic uptake by endothelial cells and immune cells (monocytes, macrophages).2,3 Pinocytotic uptake is an unspecific process with high turnover rates by which essentially all extracellular components are internalized into endosomes. The endothelial pinocytosis rate has been estimated at 50 nL/h per 106 cells. With an estimated number of 6.2 × 1011 endothelial cells per person, an endocytotic whole body rate of about 0.75 L/d is expected.4,5
Related Knowledge Centers
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