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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
F16-IL2 (TeleukinTM) is an F16 monoclonal human antibody in a diabody format specific for the alternatively spliced A1 domain of tenascin C, genetically fused to two molecules of human IL-2 at the C-terminus of each light chain. It is being developed by Philogen Inc for the treatment of breast and lung cancer. L19-IL2 (DarleukinTM) is a fully human vascular targeting immunocytokine consisting of human IL-2 genetically fused to the C-terminus of each scFv domain, with a total of two IL-2 moieties per molecule. It is being developed for the treatment of metastatic renal cell carcinoma (mRCC). L19-TNF (FibromunTM) is a clinical-stage immunocytokine consisting of the L19 antibody in scFv format targeting the alternative spliced domain EDB in the tumor neovasculature, and coupled to TNF which drives the formation of a homotrimeric structure. At the time of writing, L19-TNF is in Phase III clinical trials for the treatment of advanced or metastatic soft tissue sarcoma in combination with doxorubicin. There are many other examples of immunoconjugates in development such as NHS-IL2LT (Selectikine™), anti-CEA-IL2v (Cergutuzumab amunaleukinTM), and anti-FAP-IL2v (RO6874281).
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
Many studies of neutralizing mAbs were generated from mouse hybridoma technology; however, there is an increasing trend toward obtaining therapeutic antibody leads directly from humans. Human antibody leads are thought to be superior to antibodies derived from animals as they are indicative of the human response to pathogens. The strategy of screening for heterosubtypic human antibody leads prior to their selection and stable production also allows efforts to be focused on mAbs with the greatest possibility of success. This strategy was recently employed successfully in the identification of the first mAb, designated FI6, which neutralizes both group 1 and group 2 HA. In this study, the authors screened a total of 100,000 plasma cells from eight A(H1N1)pdm09 exposed or vaccinated donors. Only four plasma cells from a single donor were selected based on their ability to bind to group 1 and group 2 HA. These four plasma cells were then found to produce the identical FI6 mAb, highlighting the scarcity of naturally occurring broadly heterosubtypic antibodies after infection or vaccination [103].
Targeting Fc effector function in vaccine design
Published in Expert Opinion on Therapeutic Targets, 2021
Simone I. Richardson, Penny L. Moore
Perhaps some of the most convincing evidence that Fc effector function is a significant ally in protection from various diseases is the observation that many mAbs require Fc receptor binding for optimal efficacy. This observation is commonly made by abrogating or enhancing receptor binding through the introduction of mutations into the Fc of mAbs. Fc dependence for protection from HIV has been observed in animal models where antibodies unable to bind Fc receptors showed significantly less protection in non-human primates (NHPs) [13], whereas antibodies with enhanced binding to Fc receptors showed greater protection in humanized mice [12]. The exact contribution of the Fc of bNAbs against HIV infection in vivo has been estimated at 21–45% in rhesus macaques and humanized mice [14,43]. Similarly, in influenza, FI6, an hemagglutinin (HA) stalk-directed bNAb deficient in binding to Fc receptors, in contrast to the fully functional antibody, was only partially protective in mice and ferrets, indicating that the ability to protect is partly Fc mediated [44]. Both HA head and HA stalk specific bNAbs required Fc binding for optimal protection in a mouse model expressing human Fcγ receptors [10,45]. This has been also been shown in mice for mAbs targeting Ebola virus [12,46], Chikungunya virus [47] and Zika virus [48]. As for many of these diseases, protection by several SARS-CoV-2 mAbs in hamsters did not completely correlate with their capacity to neutralize in vitro and is dependent on Fc receptor binding [49].
Development of broadly reactive influenza vaccines by targeting the conserved regions of the hemagglutinin stem and head domains
Published in Expert Review of Vaccines, 2020
Nina M.C. De Jong, Aafke Aartse, Marit J. Van Gils, Dirk Eggink
Broadly neutralizing antibodies with an even wider binding spectrum have been shown to recognize and neutralize both group 1 and group 2 viruses, such as CT149 [26], FI6v3 [27], 3I14 [28], and MEDI8852 [29]. These broadly neutralizing antibodies were all isolated from human cells using different methods (Table S1). Interestingly, FI6v3 and MEDI8852 are the optimized versions of the human antibodies FI6 and FY1, respectively. For these two antibodies the unnecessary somatic mutations were eliminated via random mutagenesis of the variable region of the antibodies in order to increase the affinity toward H1 and H3 [27,29].
Effect of poly(ethylene glycol) content and formulation parameters on particulate properties and intraperitoneal delivery of insulin from PLGA nanoparticles prepared using the double-emulsion evaporation procedure
Published in Pharmaceutical Development and Technology, 2018
Yusuf A. Haggag, Ahmed M. Faheem, Murtaza M. Tambuwala, Mohamed A. Osman, Sanaa A. El-Gizawy, Barry O’Hagan, Nigel Irwin, Paul A. McCarron
Insulin-loaded NP (F16) prepared by sonication resulted in a decrease in %EE compared to NP prepared by homogenization (F9). Size and PDI values were significantly (p < .01) higher. The release profile of F16 showed significantly higher initial and higher total amounts of insulin released (p < .05) when compared to similar data from F9 (Figure 7). Release data for F9 and F16 follow a profile that is typical of drug delivery systems that display Higuchi kinetics. Indeed, fitting cumulative percentage drug release data in Figure 7 to the square root of time (data not shown) confirmed this assumption.