Mutations resulting in the formation of hyperactive complement convertases support cytocidal effect of anti-CD20 immunotherapeutics
Felberg, Anna ; Urban, Aleksandra ; Borowska, Anna ; Stasiłojć, Grzegorz ; Taszner, Michał ; Hellmann, Andrzej ; Blom, Anna Maria LU
and Okrój, Marcin
LU
(2019)
In Cancer Immunology, Immunotherapy
68(4).
p.587-598
- 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... (More)
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.
(Less)
- author
- Felberg, Anna
; Urban, Aleksandra
; Borowska, Anna
; Stasiłojć, Grzegorz
; Taszner, Michał
; Hellmann, Andrzej
; Blom, Anna Maria
LU
and Okrój, Marcin
LU
- organization
- publishing date
- 2019-02-06
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Chronic lymphocytic leukemia, Complement, Immunotherapy, Ofatumumab, Rituximab
- in
- Cancer Immunology, Immunotherapy
- volume
- 68
- issue
- 4
- pages
- 587 - 598
- publisher
- Springer
- external identifiers
-
- pmid:30725204
- scopus:85061206615
- ISSN
- 0340-7004
- DOI
- 10.1007/s00262-019-02304-0
- language
- English
- LU publication?
- yes
- id
- 82195dbc-25b0-4633-9fc2-8d16cad8f147
- date added to LUP
- 2019-02-20 09:20:28
- date last changed
- 2024-04-15 23:34:54
@article{82195dbc-25b0-4633-9fc2-8d16cad8f147,
abstract = {{<p>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.</p>}},
author = {{Felberg, Anna and Urban, Aleksandra and Borowska, Anna and Stasiłojć, Grzegorz and Taszner, Michał and Hellmann, Andrzej and Blom, Anna Maria and Okrój, Marcin}},
issn = {{0340-7004}},
keywords = {{Chronic lymphocytic leukemia; Complement; Immunotherapy; Ofatumumab; Rituximab}},
language = {{eng}},
month = {{02}},
number = {{4}},
pages = {{587--598}},
publisher = {{Springer}},
series = {{Cancer Immunology, Immunotherapy}},
title = {{Mutations resulting in the formation of hyperactive complement convertases support cytocidal effect of anti-CD20 immunotherapeutics}},
url = {{http://dx.doi.org/10.1007/s00262-019-02304-0}},
doi = {{10.1007/s00262-019-02304-0}},
volume = {{68}},
year = {{2019}},
}