Friday, October 10, 2014

White Paper: T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation

At our upcoming Immunogenicity for Biotherapeutics Event, Anne S. De Groot will be joining us to present New Approaches & Emerging Technologies To Overcome The Effects Of Immunogenicity.

Ahead of that presentation, she shared a few of her recent research papers, including one titled T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation.   In this paper, they look at the strategies to assess immune responses to protein therapeutics during the preclinical and clinical phase of development.  In this particular white paper, they focus on Td contributions to immunogenicity.

Here is an excerpt:
1.1. The immunogenicity of protein therapeutics
Since the approval of the first recombinant biological therapeutic, insulin, in October 1982, more than 165 biotherapeutic agents have entered the marketplace and have generated an estimated $99 billion in sales worldwide [1], [2], [3] and [4]. Therapeutic biologics offer the advantages of increased specificity and reduced toxicity compared to small molecules. However, when administered to patients, these protein-based drugs have the potential to elicit immune responses that may directly impact drug safety, efficacy, and potency. For example, anti-drug antibodies (ADA) that develop in response to a therapeutic protein may alter the drug's pharmacokinetic profile and abrogate its pharmacodynamic effect (neutralizing activity) [5], [6], [7] and [8].

Immune responses to proteins are characterized by the generation of antibodies (humoral immune response) that could be T cell dependent or independent. T-independent antibody responses may be generated when B cells recognize a repeated pattern (motif) in the therapeutic protein and respond by transiently producing low-affinity, predominately IgM antibodies [9]. Antibodies that are generated in conjunction with T cell help are referred to as T cell-dependent or thymus-dependent (Td) antibodies. This process, described in the next section, involves a complex interplay among antigen presenting cells, T cells, secreted cytokines, and B cells, emphasizing the importance of genetic factors such as HLA haplotype expression and T cell/B cell repertoire in immune responses to administered proteins. Thus, measurement of ADA IgG responses usually indicates that T cells are involved in the immune response to the protein. Moreover, a number of clinical studies now suggest that high levels of T cell-driven IgG ADA have the potential to cross-react with the endogenous counterpart, an adverse effect that can have serious consequences [10], [11] and [12].

T cell responses contribute to the generation of ADA. Proteins with therapeutic potential are produced in cell lines that are derived from a variety of sources, including mammals (both human and non-human), insects, bacteria, plants, yeast, and viruses. Small differences in the protein sequence and/or post-translational modifications (e.g., glycosylation, oxidation, deamidation, acylation, and alkylation) can contribute to the immunogenic potential of the therapeutic protein. Furthermore, the manufacturing process may involve multiple steps (e.g., regulation of gene expression, purification, concentration, formulation, and long-term stabilization) to produce recombinant proteins of sufficient quantity and quality to meet clinical release criteria. At each of these steps, there is potential for the introduction of biochemical or biophysical modifications into the molecules that may influence the immunogenicity profile of the biologic product. While these aspects of protein production may not impact function of the therapeutic protein, modifications inherent in the manufacturing process can have a major impact on host immune responses. For example, consider the case of Erbitux, a protein with non-human type glycosylations that caused anaphylaxis in selected patients who had pre-existing antibodies targeting these carbohydrate structures [13] and [14]. Host cell proteins derived from recombinant protein-producing cell lines may co-purify with a therapeutic product to become part of the final formulation [15] and [16]. These impurities, even in small quantities, have the potential to stimulate an unwanted immune response. In at least one recent case, they induced anti-host cell protein antibodies and contributed to the suspension of a clinical trial [15] and [16].

Read the full paper here. 

If you'd like to join Annie at Immunogenicity for Biotheraputics this coming October 20-22 in Boston, as a reader of this blog, when you register to join us and mention code XP1938BLOG to save $100 off the current rate.

Follow the jump for the references.

[1] D.S. Dimitrov
Therapeutic proteins
Methods Mol. Biol., 899 (2012), pp. 1–26
[2] W.R. Strohl, D.M. Knight
Discovery and development of biopharmaceuticals: current issues
Curr. Opin. Biotechnol., 20 (2009), pp. 668–672
[3] G. Walsh
Biopharmaceutical benchmarks 2010
Nat. Biotechnol., 28 (2010), pp. 917–924
[4] M.D. Barbosa
Immunogenicity of biotherapeutics in the context of developing biosimilars and biobetters
Drug Discov. Today, 16 (2011), pp. 345–353
[5]K.U. Eckardt, N. Casadevall
Pure red-cell aplasia due to anti-erythropoietin antibodies
Nephrol. Dial. Transplant., 18 (2003), pp. 865–869
[6]S.M. Tatarewicz, X. Wei, S. Gupta, D. Masterman, S.J. Swanson, M.S. Moxness
Development of a maturing T-cell-mediated immune response in patients with idiopathic Parkinson's disease receiving r-metHuGDNF via continuous intraputaminal infusion
J. Clin. Immunol., 27 (2007), pp. 620–627
[7] V. Jawa, M. Hokom, Z. Hu, N. El-Abaadi, Y. Zhuang, D. Berger, S. Gupta, S.J. Swanson, N. Chirmule
Assessment of immunogenicity of romiplostim in clinical studies with ITP subjects
Ann. Hematol., 89 (2010), pp. S75–S85
[8] G. Shankar, C. Pendley, K.E. Stein
A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs
Nat. Biotechnol., 25 (2007), pp. 555–561
[9]M. Sauerborn, E. van de Vosse, D. Delawi, J.T. van Dissel, V. Brinks, H. Schellekens
Natural antibodies against bone morphogenic proteins and interferons in healthy donors and in patients with infections linked to type-1 cytokine responses
J. Interferon Cytokine Res., 31 (2011), pp. 661–669
[10] N. Casadevall, J. Nataf, B. Viron, A. Kolta, J.J. Kiladjian, P. Martin-Dupont, P. Michaud, T. Papo, V. Ugo, I. Teyssandier, B. Varet, P. Mayeux
Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin
N. Engl. J. Med., 346 (2002), pp. 469–475
[11] J. Li, C. Yang, Y. Xia, A. Bertino, J. Glaspy, M. Roberts, D.J. Kuter
Thrombocytopenia caused by the development of antibodies to thrombopoietin
Blood, 98 (2001), pp. 3241–3248
[12]F. Baert, M. Noman, S. Vermeire, G. Van Assche, D.H.G., A. Carbonez, P. Rutgeerts
Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease
N. Engl. J. Med., 348 (2003), pp. 601–608
[13]C.H. Chung, B. Mirakhur, E. Chan, Q.T. Le, J. Berlin, M. Morse, B.A. Murphy, S.M. Satinover, J. Hosen, D. Mauro, R.J. Slebos, Q. Zhou, D. Gold, T. Hatley, D.J. Hicklin, T.A. Platts-Mills
Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose
N. Engl. J. Med., 358 (2008), pp. 1109–1117
[14]S.K. Singh
Impact of product-related factors on immunogenicity of biotherapeutics
J. Pharm. Sci., 100 (2011), pp. 354–387
[15]A.H. Gutierrez, L. Moise, A.S. De Groot
Of [hamsters] and men: a new perspective on host cell proteins
Hum. Vaccin. Immunother., 8 (2012)
[16]K. Lewis
Inspiration Biopharmaceuticals Announces Clinical Hold of Clinical Trials Evaluating IB1001 for the Treatment and Prevention of Bleeding in Hemophilia B Inspiration Biopharmaceuticals (2012)

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