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Impact of Immunogenicity on the Pharmacokinetics and Pharmacodynamics of Biosimilars

06 Apr 2023

Due to An increasing utilization and approvals of biosimilars, immunogenicity has become a significant concern which needs to be assessed due to its potential impact on efficacy and safety of the molecule. With the use of biological products, individuals sometimes tend to develop immunogenicity due to which the body's immune system produces anti-drug antibodies (ADA) which further binds to various epitopes of the circulating molecule leading to varying its effects in terms of pharmacokinetics and/or efficacy or safety of the molecule. Some of the common factors contributing to the development of immunogenicity are selection of vector, cell expression system, protein production, purification and validation, physicochemical properties and stability profile of the molecule, patient related intrinsic/extrinsic factors and manufacturing process of the molecule.

Changes in manufacturing process, purification process or post-translational modifications such as glycosylation, phosphorylation, deamination, and oxidation can lead to formation of compounds/intermediates which might ultimately result in immune response against the drug. Furthermore, these changes can sometimes lead to changes in drug structure that can affect either antibody dependent cellular cytotoxicity (ADCC) or complement-dependent cellular cytotoxicity (CDC) hampering the efficacy profile of the molecule. Some of the publications analyzed reporting status of immunogenicity data components by reviewing the prescribing information of products approved before February 2015, which is depicted below:

Reporting Status of Immunogenicity Data Components (Reported vs. non reported)

ADA can affect the functioning of the molecule possibly by antigen/receptor binding, fragment antigen-binding region (Fab) associated functions like neutralization, receptor activation or blockade or by Fragment crystallizable region (Fc) associated functions like complement activation, ADCC or CDCC.

Basically, ADA is broadly classified as Neutralizing antibodies (NAb) and Non-Neutralizing antibodies (Non-NAb). As the name indicates, NAbs inhibits or reduces the pharmacological activity of the molecule. These anti-bodies can be identified either by an in-vitro test or animal-based bioassay method. On the contrary, Non-NAbs does not hamper the pharmacological activity of the molecule.

Further, ADA is also bifurcated as drug sustaining ADA response which reduces the clearance of the drug and thereby prolonging its elimination half-life and as clearing ADA response which increases the clearance of drug by any of the following mechanisms (but not limited to): Breakdown, circulating immune complex lattice, Reticuloendothelial system, Fc binding.

Sometimes, ADA formed against a particular mAb can cross-react with other mAbs of murine origin raising drug administration issues of the new mAb. Such ADA are termed as human anti-murine antibody (HAMA). In such cases, frequent assessment of immunogenicity profile can prevent the chances of treatment failure.

Similar to HAMA, anti-bodies can also cross-react with chimeric mAb molecules with non-human epitopes present. This type of ADA is termed as Human anti-chimeric antibody (HACA). When cross-reactivity is observed with other human sequence-based antibodies, this type of ADA is called Human anti-human antibody (HAHA).

Deviating drug levels due to ADA formation delineate an early sign of reduced efficacy during treatment course.

Commonly used ways of assessing the impact of immunogenicity on PK/PD of biologics are depicted below:

1. Wang Y, Wang J, Hon Y, Zhou L, Fang L, Ahn H. Evaluating and Reporting the Immunogenicity Impacts for Biological Products—a Clinical Pharmacology Perspective. The AAPS Journal. 2015;18(2):395-403.

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