Peptide monoclonal

After a comprehensive introduction, the basic PK/PD properties of peptides, monoclonal antibodies, antisense oligonucleotides and gene delivery vectors are reviewed. In the second part, the book covers a number of challenges and opportunities in this field such as bioanalytical methods, bioequivalence and pulmonary delivery. The text finishes with a detailed presentation of some real-life examples and case studies which should be of particular interest to the reader and integrate many of the concepts presented earlier in the text. 

Following a short introduction, the book is structured into three sections The Basics section discusses individually the pharmacokinetics of peptides, monoclonal antibodies, antisense oligonucleotides and gene delivery vectors. The subsequent Challenges and Opportunities section includes more detailed considerations on selected topics, including technical challenges such as bioanalytical... 

Some radiopharmaceuticals are rather complex dosage forms. Radiolabelled nanospheres, nanoparticles, nanocolloids, peptides, monoclonal antibodies and glass particles for radioembolisation are a few examples. Also autologous blood cells can be radiolabelled, outside or inside the body. The radiolabelling of blood cells is used in routine practice. 

A two-site immunometric assay of undecapeptide substance P (SP) has been developed. This assay is based on the use of two different antibodies specifically directed against the N- and C-terminal parts of the peptide (95). Affinity-purified polyclonal antibodies raised against the six amino-terminal residues of the molecule were used as capture antibodies. A monoclonal antibody directed against the carboxy terminal part of substance P (SP), covalently coupled to the enzyme acetylcholinesterase, was used as the tracer antibody. The assay is very sensitive, having a detection limit close to 3 pg/mL. The assay is fiiUy specific for SP because cross-reactivity coefficients between 0.01% were observed with other tachykinins, SP derivatives, and SP fragments. The assay can be used to measure the SP content of rat brain extracts. 

Tissue plasminogen activators Human growth hormone Neuroactive peptides Regulatory peptides Lymphokines Human serum albumin Gamma globulin Antihemophilic factors Monoclonal antibodies... 

Rituximab is a recombinant mouse/human chimeric monoclonal antibody whose in vitro activity varies with the number of terminal galactose moieties glycosylated to the peptide backbone at residue asparagine 301 [8]. The ability to monitor the levels of each discrete species present would allow the manufacturing process to... 

In addition to the three types of immunological product that are generally available there are two further types synthetic peptide vaccines and monoclonal antibodies. Both have been extensively investigated but neither has, as yet, a place in conventional prophylaxis or therapeutics. 

EDTA Ethylenediamine tetraacetic acid ako known as etidronic acid EE Eosinophilic eosinophils EEG Electroencephalogram EET Epoxyeicosatrienoic acid EFA Essential fatty acid EFS Electrical field stimulation EGl Monoclonal antibody specific for the cleaved form of eosinophil cationic peptide... 

Another difficulty is that a peptide may be able to bind to an existing neutralizing monoclonal antibody by an induced-fit mechanism that is somehow driven by the pre-existing structure of the antibody paratope. However, the same induced-fit process may not take place when the peptide is used as the immunogen and is confronted in the host by a large population of B cell receptors allowing a variety of other interactions. 

El-Kasmi, K. C., Deroo, S., Theisen, D. M., Brons, N. H. C. and Muller, C. P. (1999), Crossreactivity of mimotopes and peptide homologues of a sequential epitope with a monoclonal antibody does not predict crossreactive immunogenicity , Vaccine, 18, 284-290. 

TES-32 is the most abundant single protein product secreted by the parasite. It is also heavily labelled by surface iodination of live larvae (Maizels et al., 1984, 1987), and is known by monoclonal antibody reactivity to be expressed in the cuticular matrix of the larval parasite (Page et al, 1992a). TES-32 was cloned by matching peptide sequence derived from gel-purified protein to an expressed sequence tag (EST) dataset of randomly selected clones from a larval cDNA library (Loukas et al., 1999). Because of the high level of expression of TES-32 mRNA, clones encoding this protein were repeatedly sequenced and deposited in the dataset (Tetteh et al., 1999). Full sequence determination showed a major domain with similarity to mammalian C-type (calcium-dependent) lectins (C-TLs), together with shorter N-terminal tracts rich in cysteine and threonine residues. Native TES-32 was then shown to bind to immobilized monosaccharides in a calcium-dependent manner (Loukas et al., 1999). 

Sithigorngul, P., Cowden, C., Guastella, J. and Stretton, A.O.W. (1989) Generation of monoclonal antibodies against a nematode peptide extract another approach for identifying unknown neuropeptides. Journal of Comparative Neurology 284, 389-397. 

Another type of intestinal peptide transporter, hPTl, which is significantly different in sequence from PEPT1, was identified using a functionally inhibitory monoclonal antibody [99]. This transporter is widely expressed in the human GI tract and facilitates the oral absorption of pdactam antibiotics and ACE inhibitors from the intestine [18, 99]. Interestingly, we recently reported that hPTl gene expression is approximately 4-fold higher than PEPT1 in the human duodenum [4] (Fig. 11.1). 

For small molecules, natural products, peptides, oligonucleotides, gene vectors, recombinant proteins and monoclonal antibodies ... 

If a monoclonal antibody was generated by immunization with a full-length native protein rather than a peptide, then the immunized mouse will generate antibodies that recognize both linear and conformationally dependent epitopes. Only a small subset of these monoclonal antibodies will likely be useful for clinical use on formalin-fixed, paraffin-embedded tissue (FFPE) samples. Those that are useful tend to have epitopes that are linear the epitopes are not dependent on the protein s three-dimensional conformation (see Chapter 16). Therefore, for antibodies generated in response to immunization with full-length proteins, the peptides that serve as positive controls will be linear stretches of amino acids derived from the native protein sequence, as listed in protein databases. 

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