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Immunogenicity and PK/PD

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I want to talk about immunogenicity and PK/PD. Now therapeutic proteins, as you know, have antigenic potential, particularly because or particularly if the protein is derived from the animals or microorganism. The protein antibody complexation can stimulate protein clearance by the reticuloendothelial system. On the other hand, binding to antibody also or can slow down the rate of clearance, and the complex actually act as a depot for the protein and prolong the action of the biologics, and this Interferon-alpha 2a is just one example. Now antibody-induced PK change could also depend on the dose. For example, that low dose decreased clearance, and high dose actually increased the clearance. And this is the case for interleukin 6.
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So there are varying effects of immunogenicity on pharmacokinetics biologics. Let’s look at it again. Immunogenic response. When it happens, it could neutralize, it could produce neutralizing antibodies that neutralize the antigen or the biologics, which results in the loss of activity. On the other hand, the protein antibody complex could stimulate clearance or could decrease clearance. When it stimulates clearance, it results in loss of activity. But when it decreases clearance, it actually enhanced the activity. Let me talk, turn to a different subject that is the allometric scaling. This is part of the pharmacokinetics. What is the allometric scaling? It is an empirical technique to predict PK/PD relationship based on the body side, here specifically the body weight.
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Now for small molecules, this scaling is often imprecise. But for larger molecules, the proteins, the scaling is actually more predictable because of the similarity in the disposition of proteins and peptides within the mammalian species. And this equation describes the allometric scaling. Well, P is the pharmacokinetic or pharmacodynamic parameter. A is a coefficient, And B is an exponent. And W is the weight. So let’s look at this glycoprotein. When we look at clearance, by the way, after the drug is given intravenously. When you look at the clearance versus weight, there’s a good correlation between clearance and weight. If we look at the volume of steady-state and weight, there is also a very good correlation between the volume distribution and weight.
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So this graph tells us the allometric scaling for biologics is more predictable or rather predictable compared with small molecules. So allometric scaling. Let’s kind of summarize it. For small molecule drug X, the drug looks at those five, four species very differently. The mouse, the rat, the chimpanzee, and the pig. But biologics, the large molecule, Biologic Y, look at those four species not so much differently but really as one species. So that is rather interesting, allometric for small molecules is hard to predict, but for biologics is rather predictable.

Repetitive administration of protein-based therapeutics to immunocompetent patients can elicit immune responses in the form of Anti-Drug Antibodies (ADAs). One form of immune response is the activation of B cells, which produce antibodies that bind to the proteins and reduce or eliminate their therapeutic effects. The majority of ADA to therapeutic monoclonal antibodies (mAbs) are directed against the antigen-binding site of the therapeutic mAb, and hence are neutralizing. This nature of the ADA response explains why fully human antibodies can still be immunogenic. On the other hand, the complex formation of protein-ADA may culminate a depot effect which impedes the turnover of the protein. In such rare scenario, favorable therapeutic benefits may be expected. On a different subject, allometric scaling and correlation are compared between proteins and drugs.

All therapeutic proteins have antigenic potential and could elicit an immune response with the consequent production of anti-drug antibodies (ADA). The immunogenic response can be manifested in two ways: The neutralizing effect of ADA reduces or eliminates the therapeutic response or even develops undesirable adverse effects The complexation of ADA-protein impedes the turnover of the circulating protein and favors the therapeutic effect. Allometry or biological scaling is the change of scalable PK/PD attributes in relation to changes in body size. It is interesting to note that allometric scaling is more evident for proteins compared with small molecule drugs. This can be explained by “selfness” or “sameness” of protein perceived by the organisms as opposed to the vastly different small molecules.

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Pharmacotherapy: Understanding Biotechnology Products

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