Regulators requiring data on impact of antibody-dependent cellular phagocytosis to better understand mAb responses. The third of a three-part series.

Biologics are the fastest-growing segment of the biopharmaceutical market, with the primary driver monoclonal antibodies (mAbs).

Since the commercialization of the first therapeutic mAb product in 1986, 47 mAb products have been approved in the US and Europe. At the current approval rate of four new products per year, roughly 70 mAb products will be on the market by 2020, with combined worldwide sales nearly US$125 billion, suggests a recent analysis by BioProcess Technology Consultants.

The long-awaited approval this year of the US’s first biosimilar—an immune-boosting cytokine drug that mimics Sandoz’ Neuopogen—will only add to the growth. More will follow soon, especially for blockbuster mAbs. Nearly a dozen other biologics also face biosimilar competition, 11 for just the rheumatoid arthritis drug Humira, the world’s best-selling drug in 2013, according to the Wall Street Journal.

But making a biosimilar is not the same as assembling a small-molecule generic, where you can synthesize the same molecule and be confident in the results. Biologics are much more complex and difficult to characterize. They are made in living cells and even minute changes in the antibody’s structure can affect its stability, potency, immunogenicity and bioavailability.

So as the field braces for an expected surge in biopharmaceutical products, regulators in Europe and the US are busy seeking a wealth of in vitro data on the structural and functional performance of biosimilar products. This includes assessing the mechanisms of action (MOA) of the antibody biosimilars and comparing these and their immunological properties to those of the innovator drug.

Antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are two of the more commonly studied MOAs of therapeutic antibodies, but antibody-dependent cellular phagocytosis (ADCP), a neglected MOA and the subject of this three-part series, is also of interest to regulators.

Our first two articles dealt with the challenges and potential solutions in measuring ADCP function. This last installment looks at what’s been happening on the regulatory front and why it could finally raise the visibility of players like ADCP.

Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend that developers provide extensive structural and functional characterization of their products, and the US requires it for the reference product. The EMA also recommends preclinical in vitro studies that assess antibody binding to the target antigen, Fc binding and the corresponding functional assays including ADCC and CDC assays. The FDA has similar guidelines that should be followed to demonstrate biosimilarity, including the use of biological assays and binding assays as in vitro functional assays. Additionally, the FDA guidance document says such functional assays may be used to “provide additional evidence that the MOA of the two products is the same to the extent the MOA of the reference product is known.”

Neither of these documents refers to ADCP explicitly, a complicated MOA that many labs simply aren’t equipped to assess. But regulators do want a more complete picture of the potential pathways that therapeutic antibodies use to generate a certain response, particularly for biosimilars and biobetters that are modified to optimize the efficacy of the antibody on its intended target. Often such molecules have an altered MOA compared to the innovator molecule. The same “more complete picture” requirement is also being expected by regulators for first-in-class products, where the main MOA has not yet been defined.

Figure 1
Figure 1. A partially afucosylated variant of Rituximab binding to the same epitope.

Most of the MOA functions – especially for the anticancer mAbs that are IgG1-based and follow the classical pathways – are dependent on Fc receptor function. Each of the receptors mediates certain immune responses which lead to the death of the target cell, e.g. a tumor cell via a certain pathway.

Regulators seem particularly interested in the FcγRIIa receptor—thought to be the dominant player in the induction in ADCP by macrophages—and they are now requesting data on the impact of ADCP on the antibody-mediated cytotoxicity. Even the absence of a certain MOA mediated by the Fc-receptors need to be demonstrated appropriately by reliable in vitro methods. This is particularly true since certain, at first glance, minor modifications of e.g. follow-on mAbs might change the impact of the different Fc receptor functions (and thereby the main MOA) significantly towards a direction less relevant for the innovator.

What this means is that the developers of therapeutic antibodies must now find more efficient and reliable ways of assessing ADCP function than the conventional assays that have typically been used. As this series suggests, there are promising tools—such as the reporter-based surrogate approach discussed in this series—that are faster, less variable and more accurate. These in vitro assays, when applied to evaluation of specific antibodies being developed by biopharma, could help improve reflection of in vivo bioactivity during early-phase biocomparability as well as for lot release and stability.

And rid ADCP of its stepchild status.

How to cite:

Herbrand U., Surowy T., Completing the Picture. Eureka blog. May 26, 2015. Available: http://eureka.criver.com/completing-the-picture/