Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action

Sheridan, Douglas; Yu, Zhao-Xue; Zhang, Yuchun; Patel, Rekha; Sun, Fei; Lasaro, Melissa A.; Bouchard, Keith; Andrien, Bruce; Marozsan, Andre J.; Wang, Yi; Tamburini, Paul P.

doi:10.1371/journal.pone.0195909

Cited by 173 publications

(167 citation statements)

References 26 publications

(32 reference statements)

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“…A common method for engineering pH sensitive antibodies is to introduce histidine residues, which become protonated at lower pH, into the variable domains of antibodies. This strategy was used in the development of ALXN1210, a modified version of eculizumab, that harbors two variable domain histidine mutations and amino acid substitutions in the Fc domain to increase FcRn binding affinity [19]. Though ALXN1210 is reported to have prolonged PK in humans (T 1/2 � 32 days), it binds C5 with reduced affinity (17-fold reduction) at neutral pH [19], which may necessitate the administration of higher antibody concentrations to sustain suppression of C5 cleavage in vivo.…”

Section: Plos Onementioning

confidence: 99%

Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5

et al. 2020

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Complement is a key component of the innate immune system. Inappropriate complement activation underlies the pathophysiology of a variety of diseases. Complement component 5 (C5) is a validated therapeutic target for complement-mediated diseases, but the development of new therapeutics has been limited by a paucity of preclinical models to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of candidate therapies. The present report describes a novel humanized C5 mouse and its utility in evaluating a panel of fully human anti-C5 antibodies. Surprisingly, humanized C5 mice revealed marked differences in clearance rates amongst a panel of anti-C5 antibodies. One antibody, pozelimab (REGN3918), bound C5 and C5 variants with high affinity and potently blocked complement-mediated hemolysis in vitro. In studies conducted in both humanized C5 mice and cynomolgus monkeys, pozelimab demonstrated prolonged PK and durable suppression of hemolytic activity ex vivo. In humanized C5 mice, a switch in dosing from in-house eculizumab to pozelimab was associated with normalization of serum C5 concentrations, sustained suppression of hemolytic activity ex vivo, and no overt toxicity. Our findings demonstrate the value of humanized C5 mice in identifying new therapeutic candidates and treatment options for complement-mediated diseases. OPEN ACCESS Citation: Latuszek A, Liu Y, Olsen O, Foster R, Cao M, Lovric I, et al. (2020) Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5. PLoS ONE 15(5): e0231892. https://doi.org/10.

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Section: Plos Onementioning

confidence: 99%

Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5

et al. 2020

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“…This mAb incorporates a pH‐dependent recycling technology that increases half‐life and decreases dose required for efficient C5 inhibition . The modified form of Eculizumab, ALXN1210, uses a similar pH switch technology to increase recycling efficiency and drug half‐life . Unlike Eculizumab, RO7112689 also binds C5b6, the intermediate product of MAC formation, and so inhibits reactive lysis .…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of novel anti‐C5 monoclonal antibodies capable of inhibiting complement in multiple species

2019

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Summary Over the last decade there has been an explosion in complement therapies; one‐third of the drugs in the clinic or in development target C5 protein. Eculizumab, a monoclonal antibody (mAb) that binds C5 and blocks its cleavage by the convertase, is the current reference standard treatment for atypical haemolytic uraemic syndrome (aHUS) and paroxysmal nocturnal haemoglobinuria (PNH) and in clinical trials for many other diseases. Here we describe a panel of novel anti‐C5 mAb, including mAb that, like Eculizumab, are efficient inhibitors of complement but, unlike Eculizumab, inhibit across species, including human, rat, rabbit and guinea pig. Several inhibitory anti‐C5 mAb were identified and characterized for C5 binding and lytic inhibitory capacity in comparison to current therapeutic anti‐C5 mAb; three clones, 4G2, 7D4 and 10B6, were selected and further characterized for ligand specificity and affinity and cross‐species inhibitory activity. The mAb 10B6 was human‐specific whereas mAb 4G2 and 7D4 efficiently inhibited lysis by human, rabbit and rat serum, and weakly inhibited guinea pig complement; 7D4 also weakly inhibited mouse complement in vitro The rat C5‐cross‐reactive mAb 4G2, when administered intraperitoneally in a rat model of myasthenia gravis, effectively blocked the disease and protected muscle endplates from destruction. To our knowledge this is the first report of an anti‐C5 function blocking mAb that permits preclinical studies in rats.

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“…Recently, one of the first Fc engineered monoclonals aimed at enhancing Fc/FcRn (neonatal Fc receptor) interactions at pH 6.0 demonstrated a substantial improvement in half‐life and therapeutic efficacy 66,67 . Ravulizumab, a novel Fc engineered anti‐C5, developed from eculizumab, has enhanced binding to the FcRn at pH 6.0.…”

Section: Therapeutic Approaches To Treatment Of Amrmentioning

confidence: 99%

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection

et al. 2019

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Modification of pathogenic antibodies and their effector functions in autoimmune diseases or use of B cell/plasma cell‐directed anticancer therapies have illuminated the biologic relevance of B cells, plasma cells (PCs), and pathogenic antibodies and complement in alloimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines that drive dysfunctional immune responses. Current methods to reduce alloantibodies are only modestly successful. Rituximab is used for desensitization and antibody‐mediated rejection (AMR) treatment by targeting CD20 found on B‐lymphocytes. However, PCs do not express CD20, likely explaining the limited success of this approach. Intravenous immunoglobulin and plasmapheresis (PLEX) have limited success due to antibody rebound. Despite attempts to develop tolerable therapeutics for management of AMR, none, to date, have been universally accepted or obtained Food and Drug Administration approval. Lack of approved therapeutics often results in patients having a much shorter graft survival due to AMR. Repurposing drugs from autoimmunity and cancer immunotherapy has rapidly yielded important advancements in the care of AMR patients. Here we discuss emerging therapeutics aimed at prevention and treatment of AMR.

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Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action

Cited by 173 publications

References 26 publications

Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5

Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5

Development and characterization of novel anti‐C5 monoclonal antibodies capable of inhibiting complement in multiple species

Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection

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