Inmunogenicidad de Biológicos/Biosimilares

Transcription

1 Inmunogenicidad de Biológicos/Biosimilares Gilberto Castañeda Hernández Departamento de Farmacología Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional Ciudad de México

2 Statement of Possible Conflicts of Interest I am a Senior Investigator at the Center for Research and Advanced Studies of the National Polytechnic Institute in Mexico I have given lectures and participated in studies sponsored by: Abbott, AbbVie, Actelion, Amgen, Astra-Zeneca, Bayer, Boehringer-Ingelheim; Concordia, Grünenthal, Lilly, Liomont, Medix, Merck-Serono, MSD, Novartis, Pfizer, Roche, Sanofi, Sandoz, Senosiain, Silanes, Sophia, UCB I am not on the payroll or possess shares of any of these companies

3 Immunogenicity: Definition Immunogenicity is the ability of a particular substance to induce a specific immune response Humoral immune responses representing the formation of antibodies against a specific antigen Any biological/biotechnology-derived protein can trigger the production of antibodies Pineda C. et al. Assessing the immunogenicity of biopharmaceuticals. BioDrugs (2016) 30:

4 Consequences of Immunogenicity No clinical consequences Loss of response Hypersensitivity Pineda C. et al. Assessing the immunogenicity of biopharmaceuticals. BioDrugs (2016) 30:

5 Epitopes or Molecular Labels Specific structural features (amino acid and/or sugar sequences) that are recognized by the immune system. Among the best known, we have blood types (A, B, AB, O) and HLA (Human Leucocyte Antigen, used in Transplantation). If a protein presents molecular labels, it is immunogenic. Why MABs are immunogenic and endogenous antibodies are not? MABs have foreign molecular labels

6 Production of Soluble Receptors by DNA constructs, Example: Etanercept U.S. Patent number: 5,447,851

7 Mouse/Human WHO. General Policies for Monoclonal Antibodies. INN Working Document /06/2009.

8 Present Techniques: Phage Display

9 CDR-repaired antibodies. European Patent EP A3

10 Adalimumab Concentration mg/l Without AAA AAA titer AU/ml AAA titer > 100 AU/ml Weeks

11 Design of Biosimilar mabs/cepts by Reverse Engineering Innovator mab/cept DNA constructs: Genes Gene expression Post-transcription McCamish & Woollett. mabs 2011;3:

12 Antibodies directed against proteins as therapeutic antibodies or fusion proteins ADAbs directed against idiotypes can bind to the variable region of the antibody in the antigen-binding site (neutralizing) or outside (not necessarily neutralizing) Drug Idiotype Allotype Drug ADAb ADAb Ducourau E et al. Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheunatic diseases. Arthritis Res Ther 2011 Jun 22, doi: /j x

13 Inmunogenicidad y Biodisponibilidad Consequences of mab Immunogenicity: Reduced Bioavailability Anti-infliximab ADA No anti-infliximab ADA Pathological states, such as Pure Red Cell Aplasia, can only occur when immunogenicity is directed towards an endogenous mediator. However, an inadequate formulation may result in Hypersensitivity Reactions. Ducourau E et al Arthritis Res Ther 2011:13:R105.

14 Safety Problems with Products of Questionable Quality Comunicado 04/04/2012

15 EMA and/or FDA Approved mabs and Cept Biosimilars 1. CT-P13 (Remsima /Inflectra ). Infliximab. Celltrion, South Korea. 2. SB4 (Benepali ). Etanercept. Samsung-Bioepis. South Korea. 3. GP2015 (Erelzi ). Etanercept. Sandoz. Austria/Germany/ Switzerland. 4. ABP 501 (Amjevita /Solymbic ). Adalimumab. Amgen. USA. 5. SB2 (Flixabi /Renflexis ). Infliximab. Samsung-Bioepis. South Korea. 6. CT-P10 (Truxima /Tuxella /Ritemvia /Blitzima ). Rituximab. Celltrion, South Korea. 7. GP2013 (Rixathon /Riximyo ). Rituximab. Sandoz. Austria/ Germany/Switzerland. At present, all FDA/EMA approved Biosimilars have shown equivalent or reduced immunogenicity compared to innovators.

16 In all studies, immunogenicity was comparable between the non-switched and switched groups

17 Park W, et al. Ann Rheum Dis 2017;76: Kvien et al Presented at UEG Week, Vienna, October, 2016.

18 Adalimumab Concentration mg/l % Petients Showing Immunogenicity Inmunogenicidad: No todos al mismo tiempo Immunogenicity: Still a Mystery GM Bartelds et al. JAMA 2011; 305: Without AAA AAA titer AU/ml AAA titer > 100 AU/ml Weeks Weeks Why some patients develop anti-antibodies and others do not? Why the appearance of antiantibodies varies with time?

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20 C. Pineda et al. BioDrugs 30: , 2016

21 Aggregate formation can induce immunogenicity Roberts CJ. Trends Biotechnol 2014;32: Schellekens 2002 Nat Revs Drug Discov 1: Biosimilar formulation is crucial. It must avoid aggregation!

22 C. Pineda et al. BioDrugs 30: , 2016

23 C. Pineda et al. BioDrugs 30: , 2016

24 C. Pineda et al. BioDrugs 30: , 2016

25 Reference product A Biosimilar B A C B Indications with comparative clinical study? OR Indications granted by extrapolation? Biosimilar C

26 Gray Areas Why do some patients develop immunogenicity to a given biologic and others do not? Why are there variations in the time of immunogenicity appearance? There is no standardization on how to measure biosimilar immunogenicity with regard to the innovator. No FDA- or EMA-recommended methods (kits). No way to extrapolate the results from one study to another. No way to compare biosimilar immunogenicity when there is more than one.

27 Conclusions Immunogenicity is a critical feature of a biopharmaceutical, as it determines its efficacy and safety. Hence, a biosimilar must exhibit equivalent or reduced immunogenic potential with regard to the innovator. Poorly characterized products (intended copies) may result in hypersensitivity reactions representing a significant risk to patients. Standardization in immunogenicity assays for biosimilars is strongly needed.

28 Question: In no more than three words, please complete the following sentence: The immunogenic potential of a biosimilar, with regard to the innovator, must be