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Bio-similar & biobetter mAbs: Characterisation, comparability & adverse events
Roy Jefferis School of Immunity & Infection, University of Birmingham UK
GBX Summit, London, February 10-11th 2015
The first area where further innovation should be expected is product quality and productivity for upstream processes. Given the inherent complexity of biological systems any enhancement in productivity needs to be tempered by a rigorous evaluation of product attributes and quality. Although upstream production uses mature technology, intracellular processes involved in product translation, folding, post-translational modifications and secretion are still only partly understood, which would suggest there is room for further improvement.
The need for innovation in biomanufacturing.
Gottschalk U. et al. Nature Biotechnology, 30:489–492 (2012)
The “biggest change” to a therapeutic protein would be the independent development of a manufacturing process by a new manufacturer e.g. a biosimilars (i.e., a “copy” version of an already licensed originator product). EU requirements: A biosimilar mAb should be similar to the reference mAb in physicochemical and biological terms. Any observed relevant difference would have to be duly justified and could contradict the biosimilar principle.
Comparability exercise and biosimilars
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003074.pdf;
245 companies developing or already selling biosimilars 700 biosimilars approved or moving through pipeline Biosimilars sell at 20 – 30 % discount In total biosimilars are expected to account for ~ 25 % of the $100 billion worth of sales stemming from off-patent biological drugs by the end of the decade
Commercial biosimilar activity 2014:
http://www.reuters.com/article/2014/09/29/health-biotech-biosimilars-idUSL6N0RG2MA20140929
Product Biosimilars Biobetters
Humira (adalimunmab) 20 7
Remicade (infliximab) 13 8
Epogen (epoetin alfa) 82 25
Neupogen (filgrastim) 56 15
Enbrel (etanercept) 26 11
Rituxan (rituximab) 43 19
Herceptin (transuzumab) 37 14
Biosimilars and biobetters in development
Citation: Clinical Pharmacist, 6: November 2014; online | URI: 20067091
In 2009 14 biosimilar EPOs were licensed in Thailand; manufactured in Argentina, China, South Korea, and India. Concomitant with the increased penetration of biosimilars the authors noted an alarming increase in the prevalence of pure red-cell aplasia (PRCA). They were able to confirm that 23 of 30 patients referred because of loss of ESA efficacy had antibodies to erythropoietin, consistent with PRCA.
Wish JB. Kidney International 80, 11–13 (2011)
Erythropoiesis stimulating agents (ESA)
Product % Ab incidence
Humira 5 - 89
Remicade (CD) 61
Remicade (RA) 21
Campath-1H 63
GM-CSF (1) 74
GM-CSF (2) 95
IL-2 53
Immunogenicity of biopharmaceuticals:
Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products
…. it should be noted that chimeric, humanized and human monoclonal antibodies can also elicit a high rate of immunogenicity depending on the dosing regimen and patient population. … novel structural formats, including fusion proteins, ADC, bispecific or multispecific, specifically engineered antibodies etc. may elicit immune responses, as such novel structures may create neoantigens or expose cryptic epitopes.
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf
Sales 2012 - blln Herceptin (trastuzumab) – EU 2014, US 2019. $6.8 Humira (adalimumab) – EU 2018, US 2016. $9.26 Remicade (infliximab) – EU 2014, US 2018. $8.2 Rituxan (rituximab) – EU 2013,US 2018. $6.9
http://www.totalbiopharma.com/2013/05/07/biosimilar-developers-due-cash-5-therapeutic-mabs/
Patent expiry dates
The Patient Protection and Affordable Care Act
Amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act).
Signed into law by President Obama on March 23, 2010
Under the BPCI Act, a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product.
The Patient Protection and Affordable Care Act
http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/default.htm
CH3
VH
CL
VL
CH2
CH1
--S-S-- ----S-S----- ----S-S-----
Heavy chain: ~ 440 amino acids
Light chain: ~ 210 amino acids
Basic structure of an IgG antibody molecule
Antigen
binding
Fc Effector functions
Ludger
Domain structure of IgG
Fab Fab
Antigen
binding
oligosaccharide
Jefferis R. Arch. Biochem. Biophys. 526:159-662 (2012)
Ligands mediating IgG-Fc effector functions
FcγRI (IgG1,3,4) FcγRIIa* (IgG1,2,3) FcγRIIIa* (IgG1,3,4*)
phagocytosis, antibody dependent cellular cytotoxicity (ADCC), generation of superoxide, release of enzymes, immunoregulation
* dependent on FcγR polymorphisms; * dependent on glycoform
Complement: complement dependent cytotoxicity (CDC)
C1q (IgG1,3) Classical pathway
MBL (IgG1,2,3,4) Lectin pathway
FcRn (1,2,3,4) Catabolism & placental transport
Jefferis R. Arch Biochem Biophys 526:159-166 (2012) Lejeune J., Watier H et al., Bull Cancer 97:511-522 (2010)
CH3
VH
CL
VL
CH2
CH1
--S-S-- ----S-S----- ----S-S-----
- glycosylation
- deamidation
- deimination
- Met oxidation in the Fc
- C-terminal Lys processing
- hinge-region fragmentation
- glycation of Lys residues
- Pyro-Glu
Post translational and chemical modifications
Kozlowski, S. et al. Adv. Drug Delivery Reviews 58:707–72 (2006) Harris RJ. Dev Biol (Basel) 122:117-27 (2005)
Heterogeneity: 108 molecular forms possible
Transgenics: goat; sheep; cows; rabbits; pigs etc
Aves: chickens (eggs)
Yeasts: Pichia pastoris; Saccharomyces cerevisiae
Insect cells: Sf9 (baculovirus infected)
Plants: tobacco; corn; tomato; potato; moss
Bacteria: Escherichia coli; Bacillus subtilis
Glycoprotein production vehicles:
Mammalian: CHO, Sp2/0; NSO; Per.C6; HEK 293 etc
Liberia to receive Zmapp drug to treat Ebola virus
Ebola Drugs (ZMapp) produced in tobacco leaves
A Spanish priest infected with Ebola flown home for treatment
Murin CD. et al. Proc Natl Acad Sci U S A. 111:17182-7 (2014).
http://time.com/3457472/see-how-ebola-drugs-grow-in-tobacco-leaves/#3457472/see-how-ebola-drugs-grow-in-tobacco-leaves/
All product applications should contain a complete and thorough chemistry, manufacturing and controls (CMC) section that provides the necessary and appropriate information Manufacturers should provide to FDA extensive chemical, physical and bioactivity comparisons with side-by-side analyses of the "old" product and qualification lots of the "new" product. When available, fully characterized reference standards for drug substance and final container material should also be used.
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122879.htm
Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products
Physicochemical assessment of the proposed biosimilar product and the reference product should consider all relevant characteristics of the protein product (e.g., the primary, secondary, tertiary, and quaternary structure, post-translational modifications, and functional activity(ies)). The objective of this assessment is to maximize the potential for detecting differences in quality attributes between the proposed biosimilar product and the reference product.
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291134.pdf
Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products
The first biosimilar antibody therapeutic is approved by the EMA
“Remsima is a biological medicinal product similar to the reference product Remicade (infliximab) authorised in the European Union since August 1999. Studies have shown Remsima to have a comparable quality, safety and efficacy profile to Remicade (infliximab). Remsima is approved for all indications for which the innovator product Remicade (Infliximab) is approved.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003074.pdf;
Approval for Remsima demonstrates that the EMA has confidence in its ability to evaluate the comparability of biosimilar antibody products. The successful development and approval of Remsima, following EMA guidelines, may act as an incentive for the biosimilar “industry” and establishment of definitive FDA guidelines.
Blogg
Approval by the EMA as a landmark event
Beck A, Reichert JM. MAbs. 5:621-3 (2013)
Quality considerations draft guidance
Focuses on analytical studies that may be relevant to assessing the similarity between a proposed biosimilar protein product and a reference product. General principles:
Importance of extensive analytical physico-chemical and biological characterisation. Identification of lots used in the various analyses for biosimilarity determination https://www.ibbr.umd.edu/sites/default/files/public_page/Tarlov%20-%20Biomanufacturing%20Summit.pdf
Utility of a NIST mAb Reference Material
Used to distinguish analytical variability from product variability and cross-check analytical methods
Publically available, certified material with historical characterization data representative of a large class of biotherapeutic
Used to reconcile differences between orthogonal methods measuring same attribute
Used in qualification or assessment of changing analytical test methods
Used to assess performance of new analytical technologies
https://www.ibbr.umd.edu/sites/default/files/public_page/Tarlov%20-%20Biomanufacturing%20Summit.pdf
“Standard Reference Material” – distributed from NIST
frozen bulk (100 mg/mL, ≥ 98% purity) supplied in vials at 10 mg/mL & 100mg/ml (1 mL per vial) in 12.5 mM L-Histidine/12.5 mM L-Histidine HCl monohydrate (pH 6.0). Material is NOT FOR HUMAN OR ANIMAL USE
Humanized IgG1.G1m(3);Km3 expressed in NSO cells
Establishment of a “Standard Reference Material” – under the auspices of NIST and ACS
Participating laboratories
Primary Structure • Intact Mass- intact, reduced, partial digests (Fab, Fc ); • Peptide Map- native and RA; microwave, pressure; column phases
(RP, HILIC, PGC) Sequence Variant analysis
Post-translational and chemical mechanisms • Glycoanalysis ; 2-AB labeling, permethylated MALDI, and
exoglycosidase analysis of glycan composition and structure; LC-MS peptide mapping
Higher Order Structural • NMR; X-ray Crystallography; HDX; Oxidative Footprinting; Ion Mobility; Covalent crosslinking
Orthogonal techniques and assays employed
Biophysical § CD- AUC- ITC/DSC- FT-IR Analysis of the Fab, Fc, and intact mAb; DSC, DLS, membrane confined capillary electrophoresis
Separations
• cIEF; cSDS; SEC; IEX; HIC; HIC; SEC HPLC; CEX
Functional • Biacore; Elisa; Celisa; FcRn; HCP
Coefficient of absorption • AAA/OD280/ extinction coefficient
Orthogonal techniques and assays employed
“Current, State of the Art and Emerging Technologies for the Analysis of Monoclonal Antibodies”.
Editors:
John Schiel, Bioanalytical Science Group, NIST
Darryl Davis, Principal Scientist, Janssen
Oleg Borisov, Principal Scientist, Amgen
Comparability
Volume 1: Monoclonal Antibody Therapeutics: Structure, Function, and Regulatory Space
Chapter 2: Monoclonal antibodies: mechanisms of action – Roy Jefferis
Volume 2: Biopharmaceutical Characterization: The NIST mAb Case Study
Volume 3: Defining the Next Generation of Analytical and Biophysical Techniques
Jefferis R. Arch. Biochem. Biophys. 526:159-662 (2012)
The F1000Research Antibody Validation
Well validated antibodies are crucial to progress in a wide range of life science disciplines. Validating an antibody is a complex and ongoing process.
Helsby MA. et al. F1000Research 3:241 (2014)
Reproducibility: Standardize antibodies used in research
Bradbury A. & Pluckthun A. Nature 518:27-29 (2015)
Next generation biobetter anti-CD20 antibodies
Desjarlais JR. Lazar G. Exp Cell Res. 3171278-85. (2011)
Obinutuzumab
Ublituximab
Induction of tolerance or immunosuppression:
an active mechanism of self/non-self discrimination
Gonzalez S et al. Self/Nonself 2:19-25 (2011)
Operational tolerance Immunosuppression Induction of antigen-specific tolerance
Langer R. et al., PNAS 112:E156-65 (2015)
Innovation
Peanut allergy breakthrough: Children can build up tolerance
Anagnostou K. et al. Arch Dis Child. 100:68-72. (2015) Anagnostuo K et al. Lancet 383(9925):1297-304 (2014)
Induction of antigen-specific tolerance Repeated low doses of aggregate free protein
Jefferis R. Isotype & glycoform selection for antibody therapeutics. Arch Biochem Biophys 526:159-166 (2012)
Davies AM., Jefferis R., Sutton BJ. Crystal structure of deglycosylated IgG4-Fc Mol Immunol. 62:46-53 (2014)
Davies AM, Jefferis, Sutton BJ. Structural determinants of unique properties of human IgG4-Fc. J Mol Biol. 426:630-644 (2014)
Jefferis R. Monoclonal Antibodies: Mechanisms of action. In: Current state of the art for the characterisation of mAbs. Eds: D. Davis, J. Schiel & O. Borisov ACS 2015