Antibody Modelling

To guide model development, the observed data were first examined graphically to determine general characteristics and to look for trends with respect to dose, time, and the impact of anti-mAb antibodies. Models were developed using NONMEM (Version 5). Two different model types were developed the first model (MODEL 1, see Appendix 45.1) used an analytical solution (closed-form) where the nonlinearity was accounted for by allowing the model parameters to be a function of mAb dose and the titer of anti-mAb antibody, while the second model (MODEL 2, see Appendix 45.2) used differential equations to allow a more mechanistic approach to characterize the nonlinearity. For each model, three estimation methods were evaluated first-order (FO), first-order conditional estimation (FOCE), and FOCE with interaction. Various forms of between-subject variability models were evalu-... 

Bruccoleri, R. E. Novotny, J. (1992). Antibody modeling using the conformational search program CONGEN. Immunomethods 1, 96-106. 

From their antibody model of the dopamine receptor these observations could be explained at a molecular level ... 

Lysozyme -h Hy-HEL5 antibody Electrostatic steering. Mutation of charged residues close to binding site influence rate. Antibody modeled by single sphere or dumbbell. 4,68 13,81... 

Kozack R E, d Mello M J and Subramaniam S 1995 Computer modeling of electrostatic steering and orientational effects in antibody-antigen association Biophys. J. 68 807-14... 

The U.S. standard pertussis vacciae is used to standardize the potency of the whole ceU pertussis vacciae. The number of protective units Hi the vaccine is estimated for each lot from the results of simultaneous intracerebral mouse-protection tests of the vaccine being studied and the U.S. reference standard (14,17). The potency of the aceUular vaccines is estimated by then abUity to produce antibodies to the proteins Hi the vaccine Hi a mouse model. These vaccines also undergo a series of animal safety tests to ensure that the iaactivation and toxoiding steps were carried out correctiy (14,17). 

Product formation kinetics in mammalian cells has been studied extensively for hybridomas. Most monoclonal antibodies are produced at an enhanced rate during the Gq phase of the cell cycle (8—10). A model for antibody production based on this cell cycle dependence and traditional Monod kinetics for cell growth has been proposed (11). However, it is not clear if this cell cycle dependence carries over to recombinant CHO cells. In fact it has been reported that dihydrofolate reductase, the gene for which is co-amplified with the gene for the recombinant protein in CHO cells, synthesis is associated with the S phase of the cell cycle (12). Hence it is possible that the product formation kinetics in recombinant CHO cells is different from that of hybridomas. 

ACR Martin, JC Cheetham, AR Rees. Modeling antibody hypervariable loops A combined algorithm. Proc Natl Acad Sci USA 86 9268-9272, 1989. 

Figure 17.2 An example of prediction of the conformations of three CDR regions of a monoclonal antibody (top row) compared with the unrefined x-ray structure (bottom row). LI and L2 are CDR regions of the light chain, and HI is from the heavy chain. The amino acid sequences of the loop regions were modeled by comparison with the sequences of loop regions selected from a database of known antibody structures. The three-dimensional structure of two of the loop regions, LI and L2, were in good agreement with the preliminary x-ray structure, whereas HI was not. However, during later refinement of the x-ray structure errors were found in the conformations of HI, and in the refined x-ray structure this loop was found to agree with the predicted conformations. In fact, all six loop conformations were correctly predicted in this case. (From C. Chothia et al.. Science 233 755-758, 1986.)...

The normal immune response is modeled using antibodies A, B cells, helpers H, suppressors S and antigens, or viruses, V. Each of these concentrations can be either high (= 1) or low 0). The dynamics is defined as follows ... 

More complex models must carefully consider additional factors such as the receptor structure of helper T cells and allow for, what in reality, is a less than perfect lock and key match between antibody and antigen. For the latter case, Stauffer [staufF92] describes two schemes in which more than one type of antibody fits a given antigen and more than one type of antigen corresponds to a given antibody. 

The current models for the mode of action of T-cell-specific monoclonal antibodies are based on the observation that the administration of CD3 antibodies leads to a significant reduction of the number of CD3-positive T cells. On the one hand, CD3+ T cells were... 

In a mouse model for autoimmune non-obese diabetes (NOD), the full-blown diabetes could be reversed to normoglycaemia by treatment with CD3 antibodies. In these diabetes- tolerant mice, the proportions of CD4+ CD25+ regulatory T cells were increased. Moreover, the CD4+ CD25+ regulatory T cells of the tolerant mice produced high levels of... 

In addition to antibodies targeting the CD3 subunit of the TCR complex, antibodies against the a and (3 subunits of the TCR have been tested as therapeutic agents. A benefit for the treatment experimental autoimmune encephalomyelitis or collagen induced arthritis could be shown in animal models [8]. 

The application of modified electrodes for the assay of antibodies in senun preparations using redox indicators encapsuled into antigene marked liposomes attached to an electrode surface was suggested First model studies towards this goal make use of ferricyanide ions entrapped in synthetic vesicles. 

An interesting case in the perspective of artificial enzymes for enantioselective synthesis is the recently described peptide dendrimer aldolases [36]. These dendrimers utilize the enamine type I aldolase mechanism, which is found in natural aldolases [37] and antibodies [21].These aldolase dendrimers, for example, L2Dl,have multiple N-terminal proline residues as found in catalytic aldolase peptides [38], and display catalytic activity in aqueous medium under conditions where the small molecule catalysts are inactive (Figure 3.8). As most enzyme models, these dendrimers remain very far from natural enzymes in terms ofboth activity and selectivity, and at present should only be considered in the perspective of fundamental studies. 

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