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Nanocarriers as an Emerging Platform for Cancer Therapy
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Dan Peer, Jeffrey M. Karp, Seungpyo Hong, Omid C. Farokhzad, Rimona Margalit, Robert Langer
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
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Tze-Minn Mak, Ruisi Hazel Lin, Yee-Joo Tan
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
Published in Maurizio Zanetti, J. Donald Capra, 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.
Targeting Fc effector function in vaccine design
Published in Expert Opinion on Therapeutic Targets, 2021
Simone I. Richardson, Penny L. Moore
In addition, antibody engineering to improve Fc effector function has been used to enhance protection by mAbs. Specifically, reduced fucosylation of Ebola-specific mAbs was correlated with protection in guinea pigs [52], a strategy that did not improve protection against HIV in NHPs [53]. In fact, the engineering of Fc portions for enhanced receptor binding does not always translate to increased efficacy, perhaps as a result of saturation of Fc receptors on effector cells leading to their destruction [14]. This is indicative of the complex considerations necessary for antibody engineering. In addition, efficacy of antibodies against HIV has been improved by using non-neutralizing but highly potent ADCC mAbs in combination with bNAbs in vitro, an alternative strategy to make use of multiple functions to enhance protection [54], also successful against Ebola in guinea pigs [52]. Overall, these studies show the importance and potential of Fc effector function in passive immunization.