Regulatory and strategic considerations for addressing immunogenicity and related responses in biopharmaceutical development programs

AbstractThe last three decades have seen the biotherapeutic drug market evolve from promising concept to market dominance in a range of clinical indications. This growth has been spurred by the success of established drug classes like monoclonal antibodies, but also by the introduction of biosimilars, and more recently, multiple novel cell and gene therapies. Biotherapeutic drug development presents many unique challenges, but unintended immune responses are among the most common reasons for program attrition. Anti-drug antibodies can impact the safety and efficacy of drug products, and related immune responses, like the cytokine release syndrome that occurred in the infamous TGN-1412 clinical trial, can be challenging to predict with nonclinical models. For this reason, it is important that development programs proceed with a scientifically grounded and measured approach to these responses. This process begins at the discovery stage with the application of “quality by design,” continues into the clinic with the development of quality assays and management strategies, and culminates in the effective presentation of this information in regulatory documents. This review provides an overview of some of the key strategic and regulatory considerations for biotherapeutics as they pertain to immunogenicity and related responses.

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Pandemic Perspective: Commonalities Between COVID-19 and Cardio-Oncology

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.568720 ◽

2020 ◽

Vol 7 ◽

Author(s):

Sherry-Ann Brown ◽

Svetlana Zaharova ◽

Peter Mason ◽

Jonathan Thompson ◽

Bicky Thapa ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Enzyme Inhibitors ◽

Angiotensin Receptor Blockers ◽

Management Strategies ◽

Angiotensin Converting Enzyme Inhibitors ◽

Cancer Therapies ◽

Converting Enzyme ◽

Cytokine Release ◽

Converting Enzyme Inhibitors ◽

The Impact

Overlapping commonalities between coronavirus disease of 2019 (COVID-19) and cardio-oncology regarding cardiovascular toxicities (CVT), pathophysiology, and pharmacology are special topics emerging during the pandemic. In this perspective, we consider an array of CVT common to both COVID-19 and cardio-oncology, including cardiomyopathy, ischemia, conduction abnormalities, myopericarditis, and right ventricular (RV) failure. We also emphasize the higher risk of severe COVID-19 illness in patients with cardiovascular disease (CVD) or its risk factors or cancer. We explore commonalities in the underlying pathophysiology observed in COVID-19 and cardio-oncology, including inflammation, cytokine release, the renin-angiotensin-aldosterone-system, coagulopathy, microthrombosis, and endothelial dysfunction. In addition, we examine common pharmacologic management strategies that have been elucidated for CVT from COVID-19 and various cancer therapies. The use of corticosteroids, as well as antibodies and inhibitors of various molecules mediating inflammation and cytokine release syndrome, are discussed. The impact of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is also addressed, since these drugs are used in cardio-oncology and have received considerable attention during the COVID-19 pandemic, since the culprit virus enters human cells via the angiotensin converting enzyme 2 (ACE2) receptor. There are therefore several areas of overlap, similarity, and interaction in the toxicity, pathophysiology, and pharmacology profiles in COVID-19 and cardio-oncology syndromes. Learning more about either will likely provide some level of insight into both. We discuss each of these topics in this viewpoint, as well as what we foresee as evolving future directions to consider in cardio-oncology during the pandemic and beyond. Finally, we highlight commonalities in health disparities in COVID-19 and cardio-oncology and encourage continued development and implementation of innovative solutions to improve equity in health and healing.

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Prescription Drug Wholesalers: Drug Distribution and the Inspection Process (A Florida Perspective)

Journal of Pharmacy Practice ◽

10.1177/0897190006293518 ◽

2006 ◽

Vol 19 (4) ◽

pp. 196-214 ◽

Cited By ~ 3

Author(s):

David L. Laven

Keyword(s):

Supply Chain ◽

Drug Distribution ◽

Drug Market ◽

Regulatory Oversight ◽

Drug Products ◽

Enforcement Action ◽

Drug Diversion ◽

Similar Drug ◽

The Us ◽

Inspection Process

Counterfeit and diverted drugs are a growing problem not only in the US drug distribution supply chain but also in similar drug distribution supply chains the world over. These systems are being infiltrated by a growing trend in the illegal trade of pharmaceuticals, the result of activities of unscrupulous drug wholesalers, rogue Internet sites, foreign pharmacies, and organized criminal elements, all of which are motivated by huge profits. Efforts must be taken and new paradigms implemented on many fronts that will ultimately lead to maintaining the integrity of drug products and their packaging, securing the movement and safety of drug products as they travel through the US drug distribution supply chain. In addition, enhancing regulatory oversight and enforcement, increasing penalties for counterfeiters and drug diverters, advocating and pursuing heightened vigilance and awareness of counterfeit and diverted drugs, and increasing international collaboration are avenues that will aid in combating drug diversion and counterfeiting. This article will address several topics pertaining to drug wholesale distribution practices and how avenues for counterfeit and diverted drugs can permeate this process, notably through the secondary or shadow or gray drug market. Discussion will also highlight the emergence of Florida's drug pedigree laws and what were the goals to be obtained through enhanced legislative and enforcement action since 2003, coupled with the current state of these pedigree laws today as a result of action emanating from the 2006 Florida legislature (notably House bills HB371 and HB1540). Trends and developments in these major areas will be reviewed, with some analysis rendered noting strengths and areas of remaining weakness that require additional attention in the ongoing battle to stem the tide of drug diversion and counterfeiting, both nationally and within the state of Florida.

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Sphingosine 1‐phosphate induces Chemotaxis of immature dendritic cells and modulates cytokine‐release in mature human dendritic cells for emergence of Th2 immune responses

The FASEB Journal ◽

10.1096/fj.01-0625fje ◽

2002 ◽

Vol 16 (6) ◽

pp. 625-627 ◽

Cited By ~ 135

Author(s):

Marco Idzko ◽

Elisabeth Panther ◽

Silvia Corinti ◽

Anna Morelli ◽

Davide Ferrari ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Cytokine Release ◽

Immature Dendritic Cells ◽

Sphingosine 1 Phosphate ◽

Human Dendritic Cells

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Biosimilar Biologic Drugs: A Systematic Approach to Development, Manufacturing and Clinical Applications

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v10i6.4373 ◽

2020 ◽

Vol 10 (6) ◽

pp. 191-194

Author(s):

Kaiser Jay Aziz-Andersen

Keyword(s):

Quality By Design ◽

Systematic Approach ◽

Reference Product ◽

Drug Product ◽

Clinical Use ◽

Biological Characterization ◽

Biologic Drugs ◽

Drug Products ◽

Risk Benefit Assessment ◽

System Approaches

This publication addresses biosimilar biologic drugs development and future innovations. Emphasis is placed on quality system approaches to the development and availability of new biosimilar drug products presented in premarket applications. For approvals of new biosimilars, the sponsors of premarket applications must present analytical and biological characterization to demonstrate that a proposed biosimilar drug is highly similar to the licensed reference product. The premarket application protocol requires a sponsor to describe the biosimilar product’s PK/PD clinical data comparing its safety, efficacy, and immunogenicity to that of the licensed reference product. Emphasis is placed on Quality by Design (QbD), Validation, Verification, and c-GMP risk-based monitoring criteria. A brief discussion is presented on risk-benefit assessment that guides the clinical use of the new biosimilar drug product by providing patients organized data and appropriate labeling information in conformance with the new biosimilar drug’s intended clinical use. Keywords: biosimilar biologic drugs, safety, efficacy and immunogenicity, Quality by Design (QbD)

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Levels of the TNF related cytokine, LIGHT increase in hospitalized COVID-19 patients with Cytokine Release Syndrome and ARDS

10.1101/2020.07.27.20152892 ◽

2020 ◽

Author(s):

David S Perlin ◽

Inbal Zafir-Lavie ◽

Lori Roadcap ◽

Shane Raines ◽

Carl F Ware ◽

...

Keyword(s):

Immune Responses ◽

Matched Control ◽

Elevated Serum ◽

Ventilatory Support ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Limited Effect ◽

Light Levels ◽

Decoy Receptor 3 ◽

And Gender

Many COVID-19 patients demonstrate lethal respiratory complications caused by cytokine release syndrome (CRS). Multiple cytokines have been implicated in CRS, but TNFSF14 (LIGHT) has not been previously measured in this setting. In this study, we observed significantly elevated serum LIGHT levels in hospitalized COVID-19 patients as compared to healthy age and gender matched control patients. The assay detected bioavailable LIGHT unbound to the inhibitor Decoy receptor-3 (DcR3). Bioavailable LIGHT levels were elevated in patients both on and off ventilatory support, with a trend toward higher levels in patients requiring mechanical ventilation. In hospitalized patients over the age of 60, who exhibited a mortality rate of 82%, LIGHT levels were significantly higher (p=0.0209) in those who died compared to survivors. As previously reported, interleukin 6 (IL-6) levels were also elevated in these patients with significantly (p=0.0076) higher levels observed in patients who died vs. survivors, paralleling the LIGHT levels. Although attempts to block IL-6 binding to its receptor have shown limited effect in COVID-19 CRS, neutralization of LIGHT may prove to be more effective owing to its more central role in regulating antiviral immune responses.

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Papua Special Autonomic Fund Management Strategies in Sustainable Development Perspective in Papua

Konfrontasi: Jurnal Kultural, Ekonomi dan Perubahan Sosial ◽

10.33258/konfrontasi2.v8i4.165 ◽

2021 ◽

Vol 8 (4) ◽

pp. 283-292

Author(s):

Eddy Way

Keyword(s):

Sustainable Development ◽

Strategic Planning ◽

Community Participation ◽

Management Strategies ◽

Development Programs ◽

Fund Management ◽

Planning Program ◽

The People ◽

The Many ◽

Development Perspective

This article describes the implementation of special autonomy (Ots) policies in Papua through the management of the Special Autonomy Fund by formulating a strategic plan for sustainable development. Strategic Planning Program and Other Programs for Sustainable Development to Initiate and Promote Development in Papua. The purpose of this study is to analyze and understand the procedures for managing the Special Autonomy Fund. The method used is qualitative by studying, interpreting, explaining, analyzing, and interpreting various forms of procedures for managing the Special Autonomy Fund for Papua's Sustainable Development. As a result, it appears that the Papua Special Autonomy Fund's operations are weak, community participation is small, and the budget is ineffective. When the Special Autonomy Fund was implemented, there were no irregularities in its use. However, Papuans feel that there is a lack of funds for special autonomy compared to the many demands and expectations of the people in this area. Therefore, the management of these funds must be transparent and honest, and the community must also be involved in the preparation of Papua's sustainable development programs.

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Latest in Clinical Application of CAR Cell Therapy for B-cell Malignancy and Transplantation

Blood ◽

10.1182/blood.v126.23.sci-24.sci-24 ◽

2015 ◽

Vol 126 (23) ◽

pp. SCI-24-SCI-24

Author(s):

Crystal L. Mackall

Keyword(s):

Clinical Trials ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

B Cell ◽

Graft Failure ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Car T Cells ◽

Car T

Unparalleled remission rates in patients with chemorefractory B-ALL treated with CD19-CAR T cells illustrate the potential for immunotherapy to eradicate chemoresistant cancer. CD19-CAR therapy is poised to fundamentally alter the clinical approach to relapsed B-ALL and ultimately may be incorporated into frontline therapy. Despite these successes, as clinical experience with this novel modality has increased, so has understanding of factors that limit success of CD19-CAR T cells for leukemia. These insights have implications for the future of cell based immunotherapy for leukemia and provide a glimpse of more global challenges likely to face the emerging field of cancer immunotherapy. Five challenges limiting the overall effectiveness of CD19-CAR therapy will be discussed: 1) T cell exhaustion is a differentiation pathway that occurs in T cells subjected to excessive T cell receptor signaling. A progressive functional decline occurs, manifest first by diminished proliferative potential and cytokine production, following by diminished cytolytic function and ultimately cell death. High leukemic burdens predispose CD19-CAR T cells to exhaustion as does the presence of a CD28 costimulatory signal, while a 4-1BB costimulatory signal diminishes the susceptibility to exhaustion. This biology is likely responsible for limited CD19-CAR persistence observed in clinical trials using a CD19-zeta-28 CAR compared to that observed using a CD19-zeta-BB CAR. 2) Leukemia resistance occurs in approximately 20% of patients treated with CD19-CAR and is associated with selection of B-ALL cells lacking CD19 targeted by the chimeric receptor. Emerging data demonstrates two distinct biologies associated with CD19-epitope loss. Isoform switch is characterized by an increase in CD19 isoforms specifically lacking exon 2, which binds the scFvs incorporated into CD19-CARs currently in clinical trials. Lineage switch is characterized by a global change in leukemia cell phenotype, and is associated with dedifferentiation toward a more stem-like, or myeloid leukemia in the setting of CD19-CAR for B-ALL. These insights raise the prospect that effectiveness of immunotherapy for leukemia may be significantly enhanced by targeting of more than one leukemia antigen. 3) CAR immunogenicity describes immune responses induced in the host that can lead to rejection of the CD19-CAR transduced T cells. Anti-CAR immune responses have been observed by several groups, and mapping is underway to identify the most immunogenic regions of the CAR, as a first step toward preventing this complication. 4) The most common toxicities associated with CD19-CAR therapy are cytokine release syndrome, neurotoxicity and B cell aplasia. Cytokine release syndrome is primarily observed in the setting of high disease burdens and efforts are underway to standardize grading and treatment algorithms to diminish morbidity. Increased information is needed to better understand the neurotoxicity observed in the context of this therapy. Although clinical data is limited, B cell aplasia appears to be adequately treated with IVIG replacement therapy. 5) Technical graft failure (e.g. inadequate expansion/transduction) is a challenge that has received limited attention, primarily since many trials have not reported the percentage of patients in whom adequate products could not be generated. We have observed that technical graft failure is often associated with a high frequency of contaminating myeloid populations in the lymphocyte product and selection approaches designed to eradicate myeloid populations have resulted in improved T cell expansion and transduction. These results suggest that optimization of lymphocyte selection may diminish the incidence of technical graft failure. Disclosures Mackall: Juno: Patents & Royalties: CD22-CAR. Off Label Use: cyclophosphamide.

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T Cells Expressing a Novel Fully-Human Anti-CD19 Chimeric Antigen Receptor Induce Remissions of Advanced Lymphoma in a First-in-Humans Clinical Trial

Blood ◽

10.1182/blood.v128.22.999.999 ◽

2016 ◽

Vol 128 (22) ◽

pp. 999-999 ◽

Cited By ~ 17

Author(s):

Jennifer N. Brudno ◽

Victoria Shi ◽

David Stroncek ◽

Stefania Pittaluga ◽

Jennifer A. Kanakry ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Low Dose ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Car T Cells ◽

Car T ◽

Low Dose Chemotherapy ◽

Cd19 Expression

Abstract Background: Chimeric antigen receptors (CARs) are fusion proteins that combine antigen-recognition domains and T-cell signaling domains. T cells genetically modified to express CARs directed against the B-cell antigen CD19 can cause remissions of B-cell malignancies. Most CARs in clinical use contain components derived from murine antibodies. Immune responses have been reported to eliminate CAR T cells in clinical trials, especially after second infusions of CAR T cells (C. Turtle et al., Journal of Clinical Investigation, 2016). These immune responses could be directed at the murine components of CARs. Such immune responses might limit the persistence of the CAR T cells, and anti-CAR immune responses might be an especially important problem if multiple infusions of CAR T cells are administered. Development of fully-human CARs could reduce recipient immune responses against CAR T cells. Methods: We designed the first fully-human anti-CD19 CAR (HuCAR-19). The CAR is encoded by a lentiviral vector. This CAR has a fully-human single-chain variable fragment, hinge and transmembrane regions from CD8-alpha, a CD28 costimulatory domain, and a CD3-zeta T-cell activation domain. We conducted a phase I dose-escalation trial with a primary objective of investigating the safety of HuCAR-19 T cells and a secondary objective of assessing anti-lymphoma efficacy. Low-dose chemotherapy was administered before HuCAR-19 T-cell infusions to enhance CAR T-cell activity. The low-dose chemotherapy consisted of cyclophosphamide 300 mg/m2 daily for 3 days and fludarabine 30 mg/m2 daily for 3 days on the same days as cyclophosphamide. HuCAR-19 T cells were infused 2 days after the end of the chemotherapy regimen. Patients with residual lymphoma after a first treatment were potentially eligible for repeat treatments if dose-limiting toxicities did not occur with the first treatment. Repeat infusions were given at the same dose level as the first infusion or 1 dose level higher than the first infusion. Findings: A total of 11 HuCAR-19 T-cell infusions have been administered to 9 patients; 2 patients received 2 infusions each. So far, there is an 86% overall response rate (Table). Grade 3 adverse events (AEs) included expected cytokine-release syndrome toxicities such as fever, tachycardia, and hypotension. Corticosteroids were used to treat toxicity in Patient 3. The interleukin-(IL)-6 receptor antagonist tocilizumab was used to treat toxicity in Patient 4, and both tocilizumab and corticosteroids were used to treat toxicity in Patient 8. Only 1 of 8 evaluable patients, Patient 3, has experienced significant neurological toxicity to date. This patient experienced encephalopathy that was associated with a cerebrospinal fluid (CSF) white blood cell count of 165/mm3. Almost all of the CSF white cells were CAR T cells, and the CSF IL-6 level was elevated. All toxicities have resolved fully in all patients. In Patient 1, tumor biopsies revealed a complete loss of CD19 expression by lymphoma cells after 2 HuCAR-19 T-cell infusions, which to our knowledge is the first documented complete loss of CD19 expression by lymphoma after anti-CD19 CAR T-cell therapy. This loss of CD19 expression was associated with lymphoma progression. After first CAR-19 T-cell infusions, HuCAR-19 cells were detectable in the blood of every patient. The median peak number of blood CAR+ cells was 26/microliter (range 3 to 1005 cells/microliter). Blood HuCAR-19 cells were detected after second infusions in the blood of both patients who received second infusions. Patient 1 obtained a partial response after a second infusion after only obtaining stable disease after a first infusion. We detected elevations of inflammatory cytokines including IL-6, interferon gamma, and IL-8 in the serum of patients experiencing clinical toxicities consistent with cytokine-release syndrome. Interpretation: T cells expressing HuCAR-19 have substantial activity against advanced lymphoma, and infusions of HuCAR-19 T cells caused reversible toxicities attributable to cytokine-release syndrome. Disclosures Kochenderfer: Kite Pharma: Patents & Royalties, Research Funding; bluebird bio: Patents & Royalties, Research Funding.

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