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Immunization
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Michael F. Para, Susan L. Koletar, Carter L. Diggs
The first step in developing synthetic polypeptide vaccines is identification of relevant “protection-inducing′′ antigens and epitopes. Next, the amino acid sequence is determined, and the critical epitope is then synthesized chemically. The polypeptide, when attached to an appropriate carrier, induces production of antibody with specificity to the primary amino acid sequence. Induction of a protective immune response is not solely related to the primary amino acid sequence of an antigen however. Antibodies to conformational determinants of the antigen expressed on the native pathogen may also be important. Though no synthetic polypeptide vaccines have been approved for use, some have been tested in man under controlled conditions.
Polymer Materials for Oral and Craniofacial Tissue Engineering
Published in Vincenzo Guarino, Marco Antonio Alvarez-Pérez, Current Advances in Oral and Craniofacial Tissue Engineering, 2020
Iriczalli Cruz Maya, Vincenzo Guarino
Zein is a vegetable protein found in the endosperm of corn that has been explored for tissue engineering and drug delivery application due to its excellent biocompatibility (Dong et al. 2004; Zhang et al. 2016). The amino acid sequence is characterized by hydrophobic and neutral amino acids, and sole polar amino acids. Due to its composition, zein is a hydrophobic protein, which may contribute to controlling the material degradation for tissue engineering, and allowing longer and sustained release of drugs as carrier (Ali et al. 2014; Zhang et al. 2016).
Monoclonal Antibodies Used for the Diagnosis of the Small Round Cell Tumors of Childhood
Published in John T. Kemshead, Pediatric Tumors: Immunological and Molecular Markers, 2020
J.T. Kemshead, J. Clayton, K. Patel
Using DNA sequencing techniques, it is possible to predict the amino acid sequence of a particular gene. Based on this sequence it is possible to produce synthetic peptides that can be used as immunogens. To determine the amino acid sequence of peptides to be synthesized, a hydrophobicity plot (Figure 1) is often produced to determine sequences that lie in either particular hydrophilic or hydrophobic regions of the molecule.12 Synthetic peptides are then usually linked to a carrier molecule such as Keyhole Limpet Hemocyanin to render them more immunogenic. Antisera and/or monoclonal antibodies produced in this way can be purified by affinity chromatography, as it is possible to obtain the synthetic peptide/immunogen in relatively large amounts. Examples of antisera prepared by this approach are reagents recognizing oncogene products such as the C-myc13 and N-myc proteins. While the expression of the C-myc gene occurs in a relatively wide variety of tumors/tissues, the N-myc gene product is far more restricted. (See Garson et al., Chapter 10.)
Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity
Published in mAbs, 2023
Xinghua Pang, Zhaoliang Huang, Tingting Zhong, Peng Zhang, Zhongmin Maxwell Wang, Michelle Xia, Baiyong Li
Expression of PD-1 and CTLA-4 in different cancers were examined in The Cancer Genome Atlas (TCGA) PanCan Atlas studies. As shown in Figure 1a, there was a significantly positive correlation between the mRNA expression levels of PD-1 and CTLA-4 in breast, lung, stomach, colorectal, liver, cervical, head and neck, and ovarian cancer (Pearson: R = 0.74, P < 2.2e-16). Based on the co-expression status in tumors, cadonilimab was designed as a symmetrical tetravalent bispecific anti-PD-1/CTLA-4 antibody, constructed using Akeso Biopharma PD-1 antibody penpulimab (AK105) and Akeso Biopharma CTLA-4 antibody quavonlimab (AK107) (Figure 1b). The full amino acid sequence with annotation is shown in Table 1. It is composed of two heavy chains of the IgG1 subclass and two light chains of the kappa subclass, which are covalently linked through disulfide bonds, and the Fc null was designed to eliminate Fc receptors-mediated effector function. Cadonilimab has two N-linked glycosylation sites, Asn298 on Fc domain and Asn524 on the scFv domain, and contains 1,854 amino acids and has an overall molecular weight of approximately 200 kDa including oligosaccharides. This molecular design has been described in the US Patent 16327076.13 The tetravalent design of anti-PD1/CTLA-4 bispecific antibody is postulated to gain enhanced binding avidity in tumor tissues based on high-level co-expression of the targets.
Challenges in antibody structure prediction
Published in mAbs, 2023
Monica L. Fernández-Quintero, Janik Kokot, Franz Waibl, Anna-Lena M. Fischer, Patrick K. Quoika, Charlotte M. Deane, Klaus R. Liedl
Predicting the three-dimensional (3D) structure of a protein based solely on the amino-acid sequence is one of the grand challenges in the field of protein structure prediction.1 Accurate prediction of the 3D structure of a protein is critical to understand its function, as the shape of the protein determines its properties and ultimately its function. To determine the state-of-the-art methods in protein structure prediction, the biennial community-based benchmarking experiment “Critical Assessment of methods in protein Structure Prediction (CASP)” was established.2–4 In CASP14 (2020), DeepMind showcased AlphaFold2, a program based on artificial intelligence (AI) that directly processes multiple sequence alignments.5 Comparable accuracies in predicting protein structures can also be achieved with other methods including RoseTTAFold,6 and specialized tools for antibodies which incorporate the recent advances.7–9 Those tools are highly accurate based on global measures, often with root mean square deviations (RMSDs) to the crystal structure of less than 1 Å. However, there are often higher inaccuracies in specific parts of the protein that should be carefully reviewed.10,11 Post-translational modifications are omitted, but can sometimes be added afterwards.12 Furthermore, the accuracy for multimers, such as antibodies, is still lower.13 Additional challenges can arise for antibodies since VDJ recombination events do not follow the classical pathway of evolution.14
Phosphorus containing analogues of SAHA as inhibitors of HDACs
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Michael D. Pun, Hsin-Hua Wu, Feyisola P. Olatunji, Britany N. Kesic, John W. Peters, Clifford E. Berkman
Our inhibitor selectivity experiments focussed on the Class-I HDACs (HDAC1, 2, 3, and 8). The HDAC isoforms 3 and 8 were chosen from this class due to the differences in their sequence and structure. Both of these enzymes are present in the cell nucleus and use zinc as a cofactor for catalytic activity. There are 4 key differences in the active site amino acid sequence suggesting that there is a selectivity towards substrates24. HDAC8 contains a flexible L1 loop made up of 7 amino acids that form a hydrophobic secondary pocket adjacent to the active site25. This pocket has been exploited for HDAC8-specific inhibitor research and has led to “L shaped” molecules with improved activity against HDAC826. These HDACs are clinically relevant due to HDAC 8 being overexpressed in T-Cell leukaemia and Neuroblastoma27,28. HDAC3, however, is associated with neurodegenerative diseases such as Alzheimer’s disease.