Downhill running does not alter blood C1q availability or complement-dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitro
Abstract Complement-dependent cytotoxicity (CDC) is a primary mechanism-of-action of monoclonal antibody (mAb) immunotherapies used to treat haematological cancers, including rituximab and daratumumab. However, mAb efficacy may be limited by reduced bioavailability of complement C1q – which activate...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-11-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-79690-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846165232934715392 |
|---|---|
| author | Harrison D. Collier-Bain Frankie F. Brown Adam J. Causer Lois Ross Daniela Rothschild-Rodriguez Noah Browne Rachel Eddy Kirstie L. Cleary Juliet C. Gray Mark S. Cragg Sally Moore James Murray James E. Turner John P. Campbell |
| author_facet | Harrison D. Collier-Bain Frankie F. Brown Adam J. Causer Lois Ross Daniela Rothschild-Rodriguez Noah Browne Rachel Eddy Kirstie L. Cleary Juliet C. Gray Mark S. Cragg Sally Moore James Murray James E. Turner John P. Campbell |
| author_sort | Harrison D. Collier-Bain |
| collection | DOAJ |
| description | Abstract Complement-dependent cytotoxicity (CDC) is a primary mechanism-of-action of monoclonal antibody (mAb) immunotherapies used to treat haematological cancers, including rituximab and daratumumab. However, mAb efficacy may be limited by reduced bioavailability of complement C1q – which activates the complement classical pathway following interactions with mAb-opsonised target cells. C1q is secreted by phagocytes upon recruitment to sites of muscle damage to facilitate muscular repair, hence we hypothesised that muscle damaging exercise may increase C1q ‘spill-over’ into blood. Additionally, other complement proteins (e.g., C1s) have been reported to increase following ultra-endurance and resistance exercise. Taken together, we hypothesised that muscle damaging exercise could be harnessed to enhance mAb-mediated CDC. In this study, n = 8 healthy males (28 ± 5-years) completed two 45-minute treadmill running protocols: (1) a flat running protocol at a speed 15% above anaerobic threshold, and (2) a downhill running protocol (− 10% slope) at the same speed. Blood samples were collected before, immediately after, and 1-hour, 24-hours, 2-days, and 4-days after exercise. Isolated serum was assessed for C1q by ELISA, and used to measure mAb (rituximab, daratumumab) mediated CDC against two haematological cancer cell lines (Raji, RPMI-8226) in vitro. Isolated plasma was assessed for markers of inflammation (C-reactive protein [CRP]), and muscle damage (creatine kinase [CK]) by turbidimetry. C1q and CDC activity were not different between running protocols and did not change over time (p > 0.05). Significantly greater perceived muscle soreness (p < 0.001) and fluctuations observed from baseline to 24-hours post-exercise in the downhill running trial in CK (+ 171%) and CRP (+ 66%) suggests some degree of muscle damage was present. It is possible that any increase in C1q post-exercise may have been masked by the increase and subsequent interaction with CRP, which utilises C1q to facilitate muscular repair. This is the first study to investigate whether exercise can increase circulating C1q and improve mAb-mediated CDC and our findings show that downhill running exercise does not increase circulating C1q nor improve CDC in vitro. |
| format | Article |
| id | doaj-art-05c09f05aa634c8b8fd55a17bc92a64f |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-05c09f05aa634c8b8fd55a17bc92a64f2024-11-17T12:27:27ZengNature PortfolioScientific Reports2045-23222024-11-0114111310.1038/s41598-024-79690-8Downhill running does not alter blood C1q availability or complement-dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitroHarrison D. Collier-Bain0Frankie F. Brown1Adam J. Causer2Lois Ross3Daniela Rothschild-Rodriguez4Noah Browne5Rachel Eddy6Kirstie L. Cleary7Juliet C. Gray8Mark S. Cragg9Sally Moore10James Murray11James E. Turner12John P. Campbell13Department for Health, University of BathDepartment for Health, University of BathDepartment for Health, University of BathDepartment for Health, University of BathDepartment for Health, University of BathDepartment for Health, University of BathDepartment for Health, University of BathAntibody and Vaccine Group, Centre for Cancer Immunology, University of SouthamptonAntibody and Vaccine Group, Centre for Cancer Immunology, University of SouthamptonAntibody and Vaccine Group, Centre for Cancer Immunology, University of SouthamptonDepartment of Haematology, Royal United Hospitals Bath NHS Foundation TrustDepartment of Haematology, Royal United Hospitals Bath NHS Foundation TrustDepartment for Health, University of BathDepartment for Health, University of BathAbstract Complement-dependent cytotoxicity (CDC) is a primary mechanism-of-action of monoclonal antibody (mAb) immunotherapies used to treat haematological cancers, including rituximab and daratumumab. However, mAb efficacy may be limited by reduced bioavailability of complement C1q – which activates the complement classical pathway following interactions with mAb-opsonised target cells. C1q is secreted by phagocytes upon recruitment to sites of muscle damage to facilitate muscular repair, hence we hypothesised that muscle damaging exercise may increase C1q ‘spill-over’ into blood. Additionally, other complement proteins (e.g., C1s) have been reported to increase following ultra-endurance and resistance exercise. Taken together, we hypothesised that muscle damaging exercise could be harnessed to enhance mAb-mediated CDC. In this study, n = 8 healthy males (28 ± 5-years) completed two 45-minute treadmill running protocols: (1) a flat running protocol at a speed 15% above anaerobic threshold, and (2) a downhill running protocol (− 10% slope) at the same speed. Blood samples were collected before, immediately after, and 1-hour, 24-hours, 2-days, and 4-days after exercise. Isolated serum was assessed for C1q by ELISA, and used to measure mAb (rituximab, daratumumab) mediated CDC against two haematological cancer cell lines (Raji, RPMI-8226) in vitro. Isolated plasma was assessed for markers of inflammation (C-reactive protein [CRP]), and muscle damage (creatine kinase [CK]) by turbidimetry. C1q and CDC activity were not different between running protocols and did not change over time (p > 0.05). Significantly greater perceived muscle soreness (p < 0.001) and fluctuations observed from baseline to 24-hours post-exercise in the downhill running trial in CK (+ 171%) and CRP (+ 66%) suggests some degree of muscle damage was present. It is possible that any increase in C1q post-exercise may have been masked by the increase and subsequent interaction with CRP, which utilises C1q to facilitate muscular repair. This is the first study to investigate whether exercise can increase circulating C1q and improve mAb-mediated CDC and our findings show that downhill running exercise does not increase circulating C1q nor improve CDC in vitro.https://doi.org/10.1038/s41598-024-79690-8Complement-dependent cytotoxicityImmunotherapyExerciseMuscle damageComplement C1q |
| spellingShingle | Harrison D. Collier-Bain Frankie F. Brown Adam J. Causer Lois Ross Daniela Rothschild-Rodriguez Noah Browne Rachel Eddy Kirstie L. Cleary Juliet C. Gray Mark S. Cragg Sally Moore James Murray James E. Turner John P. Campbell Downhill running does not alter blood C1q availability or complement-dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitro Scientific Reports Complement-dependent cytotoxicity Immunotherapy Exercise Muscle damage Complement C1q |
| title | Downhill running does not alter blood C1q availability or complement-dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitro |
| title_full | Downhill running does not alter blood C1q availability or complement-dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitro |
| title_fullStr | Downhill running does not alter blood C1q availability or complement-dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitro |
| title_full_unstemmed | Downhill running does not alter blood C1q availability or complement-dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitro |
| title_short | Downhill running does not alter blood C1q availability or complement-dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitro |
| title_sort | downhill running does not alter blood c1q availability or complement dependent cytotoxicity of therapeutic monoclonal antibodies against haematological cancer cell lines in vitro |
| topic | Complement-dependent cytotoxicity Immunotherapy Exercise Muscle damage Complement C1q |
| url | https://doi.org/10.1038/s41598-024-79690-8 |
| work_keys_str_mv | AT harrisondcollierbain downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT frankiefbrown downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT adamjcauser downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT loisross downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT danielarothschildrodriguez downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT noahbrowne downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT racheleddy downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT kirstielcleary downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT julietcgray downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT markscragg downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT sallymoore downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT jamesmurray downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT jameseturner downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro AT johnpcampbell downhillrunningdoesnotalterbloodc1qavailabilityorcomplementdependentcytotoxicityoftherapeuticmonoclonalantibodiesagainsthaematologicalcancercelllinesinvitro |