Mutations resulting in the formation of hyperactive complement convertases support cytocidal effect of anti-CD20 immunotherapeutics

Anna Felberg , Aleksandra Urban , Anna Borowska , Grzegorz Stasiłojć , Michał Taszner , Andrzej Hellmann , Anna Maria Blom , Marcin Okrój

Abstract

Anti-CD20 monoclonal antibodies (mAbs) rituximab and ofatumumab are potent activators of the classical complement pathway, and have been approved for the treatment of B-cell malignancies. However, complement exhaustion and overexpression of complement inhibitors by cancer cells diminish their therapeutic potential. The strategies of targeting membrane complement inhibitors by function-blocking antibodies and the supplementation with fresh frozen plasma have been proposed to overcome tumour cell resistance. We present a novel approach, which utilizes gain-of-function variants of complement factor B (FB), a component of alternative C3/C5 convertases, which augment mAb-activated reactions through a positive feedback mechanism called an amplification loop. If complement concentration is limited, an addition of quadruple gain-of-function FB mutant p.D279G p.F286L p.K323E p.Y363A (or selected single mutants) results in significantly increased complement-mediated lysis of ofatumumab-resistant tumour cells, as well as the complete lysis of moderately sensitive cells. Importantly, this effect cannot be achieved by further increasing ofatumumab concentration. Potentiation of cytotoxic effect towards moderately sensitive cells was less apparent at physiological serum concentration. However, an addition of hyperactive FB could compensate the loss of cytotoxic potential of serum collected from the NHL and CLL patients after infusion of rituximab. Residual levels of rituximab in such sera, in combination with added FB, were able to efficiently lyse tumour cells. We suggest that the administration of gain-of-function variants of FB can restore cytotoxic potential of complement-exhausted serum and maximize the therapeutic effect of circulating anti-CD20 mAbs.
Author Anna Felberg (IFB / DMedB)
Anna Felberg,,
- Department of Medical Biotechnology
, Aleksandra Urban (IFB)
Aleksandra Urban,,
- Intercollegiate Faculty of Biotechnology UG
, Anna Borowska (IFB)
Anna Borowska,,
- Intercollegiate Faculty of Biotechnology UG
, Grzegorz Stasiłojć (IFB / DMedB)
Grzegorz Stasiłojć,,
- Department of Medical Biotechnology
, Michał Taszner
Michał Taszner,,
-
, Andrzej Hellmann
Andrzej Hellmann,,
-
, Anna Maria Blom
Anna Maria Blom,,
-
, Marcin Okrój (IFB / DMedB)
Marcin Okrój,,
- Department of Medical Biotechnology
Journal seriesCancer Immunology Immunotherapy, ISSN 0340-7004, (A 30 pkt)
Issue year2019
Vol68
No4
Pages587-598
Publication size in sheets0.55
Keywords in Englishcomplement, immunotherapy, rituximab, ofatumumab, chronic lymphocytic leukemia
ASJC Classification1306 Cancer Research; 2730 Oncology; 2403 Immunology; 2723 Immunology and Allergy
DOIDOI:10.1007/s00262-019-02304-0
URL https://doi.org/10.1007/s00262-019-02304-0
Languageen angielski
LicenseOther; published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)30
ScoreMinisterial score = 30.0, 31-05-2019, ArticleFromJournal
Ministerial score (2013-2016) = 30.0, 31-05-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.115; WoS Impact Factor: 2017 = 4.225 (2) - 2017=4.433 (5)
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