O‐Phospho‐ l ‐Serine mediates Hyporesponsiveness toward FVIII in Hemophilia A‐Murine Model by Inducing Tolerogenic Properties in Dendritic Cells

Fathallah, Anas M.; Ramakrishnan, Radha; Balu‐Iyer, Sathy V.

doi:10.1002/jps.24173

Cited by 6 publications

(5 citation statements)

References 30 publications

(63 reference statements)

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“…The mode of action is thought to be interstitial volume expansion in the s.c. space. We argue that OPLS may be a superior excipient to mannitol due to its immunomodulatory properties discussed elsewhere .…”

Section: Resultsmentioning

confidence: 87%

“…For this reason we argue that OPLS may be superior to mannitol as an excipient. Published data generated in our laboratory show that OPLS may have the added benefits of reducing immunogenicity toward biologics such as FVIII. This makes OPLS a multifunctional excipient that can address two of the major issues facing s.c. administration of biologics, poor bioavailability and the increased risk of immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

“…OPLS is the head group of the immune‐modulatory lipid phosphatidylserine (PS). OPLS has been studied extensively in our laboratory and shows promise as a novel adjuvant that can reduce the immunogenicity of biologics such as FVIII in our in vivo model systems . All three excipients are highly soluble in aqueous media.…”

Section: Introductionmentioning

confidence: 99%

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Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration

Fathallah

Turner

Mager

et al. 2014

Biopharm & Drug Disp

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Subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after sc administration remains a major challenge. In this work we investigated the effects of excipient dependent hyper-osmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as our animal model, we compared the effects of NaCl, mannitol and, O-Phospho-L-Serine (OPLS) on plasma concentration of rituximab over 5 days after sc administration. We observed an increase in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, as compared to isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph node in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatic, as estimated by the model, increased from 0.05 % in isotonic buffer to 13% in hyper-tonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. Our data suggests that hypertonic solutions may be a viable option to improve sc bioavailability.

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Section: Resultsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration

Fathallah

Turner

Mager

et al. 2014

Biopharm & Drug Disp

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“…Whether such alterations may also reduce the immunogenicity of therapeutic FVIII remains to be determined. Yet, the neutralization of positively charged and hydrophobic patches in FVIII using O-Phospho-l-serine (OPLS) (109,110), as well as replacement of positively charge residues by alanine in the C1 and C2 domains (107,111) reduced its immunogenicity in FVIII-deficient mice. Moreover, different inhibitory Abs, as well as clearance receptors of FVIII target positively charged residues on the C domains of the protein (112).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Binding Promiscuity of Therapeutic Factor VIII

Reyes Ruiz,

Bhale,

Venkataraman

et al. 2024

Thromb Haemost

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The binding promiscuity of proteins defines their ability to indiscriminately bind multiple unrelated molecules. Binding promiscuity is implicated, at least in part, in the off-target reactivity, non-specific biodistribution, immunogenicity and/or short half-life of potentially efficacious protein drugs, thus affecting their clinical use. In this review, we discuss the current evidence for the binding promiscuity of factor VIII (FVIII), a protein used for the treatment of hemophilia A, which cumulates poor pharmacokinetics, and elevated immunogenicity. We summarize the different canonical and non-canonical molecular interactions that FVIII may establish in the circulation and that could be responsible for its therapeutic liabilities. We also provide information suggesting that the FVIII light chain, and notably its C1 and C2 domains, could play an important role in binding promiscuity. We believe that the knowledge accumulated over years of FVIII usage could be exploited for the development of tools that predict drug efficacy and toxicity and open a mutational space to reduce the binding promiscuity of newly generated protein drugs while conserving their therapeutic efficacy.

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“…Certain skin-resident migratory cell populations, including dermal CD103 + DCs and LCs, have been targeted in such strategies to induce or expand T reg cells [205]. A reverse vaccination strategy employs SC pre-exposure to low-dose protein in the presence of OPLS to induce tolerance, and mice were rendered hyporesponsive upon reexposure to protein alone [209,210]. OPLS co-administration generates DCs with a tolerogenic profile including high secretion of regulatory TGFβ and normal migratory capability (Fig.…”

Section: Tolerance Inductionmentioning

confidence: 99%

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins

Jarvi

Balu‐Iyer

2021

BioDrugs

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The subcutaneous route of administration has provided convenient and non-inferior delivery of therapeutic proteins compared to intravenous infusion, but there is potential for enhanced immunogenicity toward subcutaneously administered proteins in a subset of patients. Unwanted anti-drug antibody response toward proteins or monoclonal antibodies upon repeated administration is shown to impact the pharmacokinetics and efficacy of multiple biologics. Unique immunogenicity challenges of the subcutaneous route have been realized through various preclinical and clinical examples, although subcutaneous delivery has often demonstrated comparable immunogenicity to intravenous administration. Beyond route of administration as a treatment-related factor of immunogenicity, certain product-related risk factors are particularly relevant to subcutaneously administered proteins. This review attempts to provide an overview of the mechanism of immune response toward proteins administered subcutaneously (subcutaneous proteins) and comments on product-related risk factors related to protein structure and stability, dosage form, and aggregation. A two-wave mechanism of antigen presentation in the immune response toward subcutaneous proteins is described, and interaction with dynamic antigen-presenting cells possessing high antigen processing efficiency and migratory activity may drive immunogenicity. Mitigation strategies for immunogenicity are discussed, including those in general use clinically and those currently in development. Mechanistic insights along with consideration of risk factors involved inspire theoretical strategies to provide antigen-specific, long-lasting effects for maintaining the safety and efficacy of therapeutic proteins.

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O‐Phospho‐ l ‐Serine mediates Hyporesponsiveness toward FVIII in Hemophilia A‐Murine Model by Inducing Tolerogenic Properties in Dendritic Cells

Cited by 6 publications

References 30 publications

Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration

Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration

Binding Promiscuity of Therapeutic Factor VIII

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins

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