Ceftriaxone-Induced Immune Hemolytic Anemia: In Vitro Reversal with Peptide Inhibitor of Complement C1 (PIC1)

Cunnion, Kenji M.; Feagin, Lisa M.; Chicella, Michael F.; Kaszowski, Cortney L.; Hair, Pamela S.; Price, Jessica; Owen, William C.

doi:10.1155/2019/4105653

Cited by 6 publications

(6 citation statements)

References 13 publications

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“…No clinical results have been published in CAD regarding ANX005, a humanized monoclonal antibody to C1q (147), and peptide inhibitor of C1 (PIC1), a small molecule that targets C1q and blocks the activation of associated serine proteases (148).…”

Section: Complement Modulationmentioning

confidence: 99%

New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

2020

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Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly Mycoplasma pneumoniae and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed.

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Section: Complement Modulationmentioning

confidence: 99%

New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

2020

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“…A recent experiment described in a case report has demonstrated in vitro reversal of CCP-mediated hemolysis initiated by serum from a patient with drug-induced AIHA. 118 No systematic human clinical study has been published.…”

Section: Complement Modulation As Therapy For Complement-driven Hemolmentioning

confidence: 99%

“…Pegcetacoplan (previously termed APL-2) is a pegylated compstatin analog designed for subcutaneous administration. 118 Systemic administration of pegcetacoplan was investigated in two phase I trials comprising 51 healthy patients. 124 Participants received vaccination as in the C1 inhibition trials.…”

Section: Complement Modulation As Therapy For Complement-driven Hemolmentioning

confidence: 99%

Novel insights into the treatment of complement-mediated hemolytic anemias

Berentsen

Hill

et al. 2019

Therapeutic Advances in Hematology

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Complement-mediated hemolytic anemias can either be caused by deficiencies in regulatory complement components or by autoimmune pathogenesis that triggers inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria (PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) is a partially complement-mediated disorder, depending on the subtype of wAIHA and the extent of complement activation. The pathophysiology, clinical presentation, and current therapies for these diseases are reviewed in this article. Novel, complement-directed therapies are being rapidly developed. Therapeutic terminal complement inhibition using eculizumab has revolutionized the therapy and prognosis in PNH but has proved less efficacious in CAD. Upstream complement modulation is currently being investigated and appears to be a highly promising therapy, and two such agents have entered phase II and III trials. Of these, the anti-C1s monoclonal antibody sutimlimab has shown favorable activity in CAD, while the anti-C3 cyclic peptide pegcetacoplan appears to be promising in PNH as well as CAD, and may also have a therapeutic potential in wAIHA.

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“…While CIIHA is a rare complication, it can progress to shock, multiorgan dysfunction, and death ( 65 ). We previously reported a case of CIIHA in a 10-year-old girl with chronic active Epstein–Barr virus disease and hemophagocytic lymphohistiocytosis ( 66 ). After chemotherapy, she was febrile and received ceftriaxone.…”

Section: Rls-0071 Efficacy In Blood-based Diseasesmentioning

confidence: 99%

“…Exogenous ceftriaxone added to the patient’s serum enhanced lysis of her erythrocytes. RLS-0071 added to the patient’s serum in the presence of ceftriaxone inhibited hemolysis in the CHUHE assay ( 66 ).…”

Section: Rls-0071 Efficacy In Blood-based Diseasesmentioning

confidence: 99%

The EPICC Family of Anti-Inflammatory Peptides: Next Generation Peptides, Additional Mechanisms of Action, and In Vivo and Ex Vivo Efficacy

Krishna¹,

Cunnion

Parker³

2022

Front. Immunol.

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The EPICC peptides are a family of peptides that have been developed from the sequence of the capsid protein of human astrovirus type 1 and previously shown to inhibit the classical and lectin pathways of complement. The EPICC peptides have been further optimized to increase aqueous solubility and identify additional mechanisms of action. Our laboratory has developed the lead EPICC molecule, PA-dPEG24 (also known as RLS-0071), which is composed of a 15 amino acid peptide with a C-terminal monodisperse 24-mer PEGylated moiety. RLS-0071 has been demonstrated to possess other mechanisms of action in addition to complement blockade that include the inhibition of neutrophil-driven myeloperoxidase (MPO) activity, inhibition of neutrophil extracellular trap (NET) formation as well as intrinsic antioxidant activity mediated by vicinal cysteine residues contained within the peptide sequence. RLS-0071 has been tested in various ex vivo and in vivo systems and has shown promise for the treatment of both immune-mediated hematological diseases where alterations in the classical complement pathway plays an important pathogenic role as well as in models of tissue-based diseases such as acute lung injury and hypoxic ischemic encephalopathy driven by both complement and neutrophil-mediated pathways (i.e., MPO activity and NET formation). Next generation EPICC peptides containing a sarcosine residue substitution in various positions within the peptide sequence possess aqueous solubility in the absence of PEGylation and demonstrate enhanced complement and neutrophil inhibitory activity compared to RLS-0071. This review details the development of the EPICC peptides, elucidation of their dual-acting complement and neutrophil inhibitory activities and efficacy in ex vivo systems using human clinical specimens and in vivo efficacy in animal disease models.

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Ceftriaxone-Induced Immune Hemolytic Anemia: In Vitro Reversal with Peptide Inhibitor of Complement C1 (PIC1)

Cited by 6 publications

References 13 publications

New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

Novel insights into the treatment of complement-mediated hemolytic anemias

The EPICC Family of Anti-Inflammatory Peptides: Next Generation Peptides, Additional Mechanisms of Action, and In Vivo and Ex Vivo Efficacy

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