Measuring of biologics for routine diagnostics

Our in-house tests (Sanquin Diagnostic Services B.V.) and MabTrack kits (Sanquin Reagents B.V.) for the routine diagnostic measurement of concentration of biologics and antibody response to these biologics (ADA) in patient serum are validated for the biologic using the international non-proprietary name.

We can measure biosimilars accurately using the tests designed to measure the originator (a.k.a. reference product) and the other way round. We would like to clarify the following:

Concentration assays for biosimilars and reference products:

• Only after a biosimilar product has been proven to be ‘highly similar’ to a reference product based on comprehensive comparability studies in terms of chemical structure, biological activity and efficacy, safety and immunogenicity profile, the regulatory agencies (EMA/FDA) allow the product on the market [1-7].
• Our assays use drug specific antibodies for detection of the biologic mainly via binding to the idiotype. As the idiotype is identical in the originator and its biosimilar (see above), our tests can measure biosimilar and originator equally well [8].

ADA tests for biosimilars and reference products:

• Prior to market release, the immunogenicity profile of ADAs to the reference and biosimilar products has to be shown to be highly similar based on comparability studies [3-4,6-7].
• Our and other studies [9-11] have shown that the antigenic response against several monoclonal antibody drug classes are similar between originator and biosimilar drugs. Moreover, the ADA are mostly restricted to the idiotype [12-14]. In our assays the idiotype of the originator is used for detection, implying the tests measure ADA to biosimilar and originator in the same way [8].

We have performed several validations for biosimilars in our assays for concentration and ADA, for example for infliximab and its biosimilar (of which one is published [8]), which showed that the assay was as suited for the reference product as for the biosimilar.

Therefore, we conclude that our in-house tests and MabTrack kits for the routine diagnostic measurement of concentration of biologics and antibody response to these biologics in patient's serum are valid for both originators and biosimilars which are on the market.

From now on we will omit a head-to-head comparison between different batches of the drug, the originator and the biosimilar, or between different biosimilars and originator for our routine diagnostic tests (concentration and ADA) for biologics.

Note: to support a biosimilar going to market, we will adhere to the appropriate regulator’s advice.

References

1.“Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Quality issues” (EMEA/CHMP/BWP/49348/2005)

2.“Guideline on development, production, characterisation and specifications for monoclonal antibodies and related substances” (EMEA/CHMP/BWP/157653/2007)

3. “Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues” (EMEA/CHMP/42832/2005/Rev1)

4. Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies – Non-clinical and Clinical Issues (EMA/CHMP/BMWP/403543/2010)

5. FDA Draft Guidance for Industry, Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations, CDER/CBER, May 2019, 2019-10667.

6. FDA Guidance for Industry, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, CDER/CBER, December 2016, FDA-2014-D-0234.

7. FDA Guidance for Industry, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, CDER/CBER, April 2015, FDA-2011-D-0605.

8. Smits LJ, Derikx LA, de Jong DJ, et al. Clinical outcomes following a switch from Remicade® to the biosimilar CT-P13 in inflammatory bowel disease patients: a prospective observational cohort study. J Crohn’s Colitis. 2016;10:1287–1293.

9. Park W, Božić-Majstorović L, Milakovic, D, et al. Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial, mAbs, 2018, 10:6, 934-943

10. Puri A, Niewiarowski A, Arai Y, et al. Pharmacokinetics, safety, tolerability and immunogenicity of FKB327, a new biosimilar medicine of adalimumab/Humira, in healthy subjects. Br J Clin Pharmacol (2017) 83 1405–1415

11. Wynne C, Altendorfer M, Sonderegger I, et al. Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE®-PK) in healthy subjects, Exp Opin Invest Drugs, 2016, 25:12, 1361-1370

12. Van Schie KA, Hart MH, de Groot ER, Kruithof S, Aarden LA, Wolbink GJ, et al. The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region. Ann Rheum Dis 2015;74:311-4.

13. Van Schie KA, Kruithof S, van Schouwenburg PA, et al. Neutralizing capacity of monoclonal and polyclonal anti-natalizumab antibodies: The immune response to antibody therapeutics preferentially targets the antigen-binding site. J Allergy Clin Immunol 2016; 139 (3): 1035-1037.

14. Goncalves J, Santos M, Acurcio R, et al. Antigenic response to CT-P13 and infliximab originator in inflammatory bowel disease patients shows similar epitope recognition. Alim Pharmacol Ther. 2018;00:1–16.