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

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Felberg, AnnaMedical University of Gdansk,University of Gdansk (author)

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

Article/chapterEnglish2019

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2019-02-06
Springer Science and Business Media LLC,2019

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LIBRIS-ID:oai:lup.lub.lu.se:82195dbc-25b0-4633-9fc2-8d16cad8f147
https://lup.lub.lu.se/record/82195dbc-25b0-4633-9fc2-8d16cad8f147URI
https://doi.org/10.1007/s00262-019-02304-0DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype
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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 CDC potential of complement-exhausted serum and maximize the therapeutic effect of circulating anti-CD20 mAbs.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
Chronic lymphocytic leukemia
Complement
Immunotherapy
Ofatumumab
Rituximab

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Urban, AleksandraUniversity of Gdansk,Medical University of Gdansk (author)
Borowska, AnnaUniversity of Gdansk,Medical University of Gdansk (author)
Stasiłojć, GrzegorzMedical University of Gdansk,University of Gdansk (author)
Taszner, MichałMedical University of Gdansk (author)
Hellmann, AndrzejMedical University of Gdansk (author)
Blom, Anna MariaLund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups(Swepub:lu)klke-abl (author)
Okrój, MarcinMedical University of Gdansk,University of Gdansk(Swepub:lu)med-moj (author)
Medical University of GdanskUniversity of Gdansk (creator_code:org_t)

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In:Cancer Immunology, Immunotherapy: Springer Science and Business Media LLC68:4, s. 587-5980340-70041432-0851

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By the author/editor: Felberg, Anna; Urban, Aleksandr ...; Borowska, Anna; Stasiłojć, Grzeg ...; Taszner, Michał; Hellmann, Andrze ...; show more...; Blom, Anna Maria; Okrój, Marcin; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

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