Challenges and approaches for the development of safer immunomodulatory biologics

Sathish, Jean G.; Sethu, Swaminathan; Bielsky, Marie Christine; Haan, Lolke de; French, Neil S.; Govindappa, Karthik; Green, James; Griffiths, C.E.M.; Holgate, Stephen T.; Jones, David; Kimber, Ian; Moggs, Jonathan G.; Naisbitt, Dean J.; Pirmohamed, Munir; Reichmann, Gabriele; Sims, Jennifer; Subramanyam, Meena; Todd, Marque D.; Laan, Jan Willem van der; Weaver, Richard J.; Park, B. Kevin

doi:10.1038/nrd3974

Cited by 149 publications

(117 citation statements)

References 172 publications

(150 reference statements)

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“…As has been shown here, detailed analysis of IgG glycoforms arising through a standard assay using a 2,6 sialic acid transferase established that a variety of AGEs, including 5-methylimidazol-4-one and aggregates, can be easily introduced if using unqualified processes. All of these side products would impede the use of this preparation in the clinic, because AGEs have the potential to be immunogenic (32,33,(39)(40)(41), and the formation of aggregates may result in the development of immune-related safety concerns, such as cytokine-release syndrome (7,42). In addition, these side products could diminish the sialic acid-dependent immunomodulatory activity.…”

Section: Discussionmentioning

confidence: 99%

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Washburn

Schwab

Ortiz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

198

161

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Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well-qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc-sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity.IVIg | sialylation | antibody | inflammation | autoimmune disease

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Section: Discussionmentioning

confidence: 99%

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Washburn

Schwab

Ortiz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

198

161

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“…The use of non-human primates is not encouraged, 25 and although closer to the human there are important differences, some of which have only come to light after serious adverse events in a clinical trial. 26 In vitro testing of human tissues to examine the distribution of a candidate TAA should be performed. Additional in vitro testing of human cells to support the expected effects of modulating the candidate antigen should be performed where applicable.…”

Section: Non-clinical Considerationsmentioning

confidence: 99%

Regulatory considerations for clinical development of cancer vaccines

Heelan

2014

Human Vaccines & Immunotherapeutics

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Cancer vaccines are aimed at stimulating an immune response to tumor tissue. There is a high level of clinical activity in this rapidly advancing field with over 1,400 trials registered on Clincaltrials.gov. The recent approval of Sipuleucel-T which is the first cancer vaccine approved in the US and EU has encouraged developers in this field. In contrast to more established approaches for treating cancer such as chemotherapy, regulatory guidelines have been developed relatively recently for cancer vaccines. These guidelines advise on general clinical requirements. As there is an increase in innovative strategies with novel products, a 2-way dialog with regulators is recommended on a case-by-case basis to justify the clinical development plan, taking into account specific quality issues related to the product(s) in development. It is important that the rationale, background and justification for the planned development is convincing when interacting with the regulatory authorities, to enable drug developers and regulators to reach agreement.

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“…Besides the clinical consequences to safety and efficacy, immunogenicity can have a significant impact on project timelines, development costs, and the regulatory approval process. The successful implementation of well-devised risk assessment and mitigation plans, resulting in significant improvement of benefit/risk profiles for promising biotherapeutics, has resulted in renewed efforts to improve prediction and mitigation of immunogenicity (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

2012 AAPS National Biotech Conference Open Forum: A Perspective on the Current State of Immunogenicity Prediction and Risk Management

Rajadhyaksha

Subramanyam

Rup

2013

AAPS J

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Abstract. The immunogenicity profile of a biotherapeutic is determined by multiple product-, process-or manufacturing-, patient-and treatment-related factors and the bioanalytical methodology used to monitor for immunogenicity. This creates a complex situation that limits direct correlation of individual factors to observed immunogenicity rates. Therefore, mechanistic understanding of how these factors individually or in concert could influence the overall incidence and clinical risk of immunogenicity is crucial to provide the best benefit/risk profile for a given biotherapeutic in a given indication and to inform risk mitigation strategies. Advances in the field of immunogenicity have included development of best practices for monitoring antidrug antibody development, categorization of risk factors contributing to immunogenicity, development of predictive tools, and development of effective strategies for risk management and mitigation. Thus, the opportunity to ask "where we are now and where we would like to go from here?" was the main driver for organizing an Open Forum on Improving Immunogenicity Risk Prediction and Management, conducted at the 2012 American Association of Pharmaceutical Scientists' (AAPS) National Biotechnology Conference in San Diego. The main objectives of the Forum include the following: to understand the nature of immunogenicity risk factors, to identify analytical tools used and animal models and management strategies needed to improve their predictive value, and finally to identify collaboration opportunities to improve the reliability of risk prediction, mitigation, and management. This meeting report provides the Forum participant's and author's perspectives on the barriers to advancing this field and recommendations for overcoming these barriers through collaborative efforts.

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Challenges and approaches for the development of safer immunomodulatory biologics

Cited by 149 publications

References 172 publications

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Regulatory considerations for clinical development of cancer vaccines

2012 AAPS National Biotech Conference Open Forum: A Perspective on the Current State of Immunogenicity Prediction and Risk Management

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