Alternative Complement Pathway Inhibition by Lampalizumab
Purpose: Lampalizumab, an antigen-binding fragment of a humanized monoclonal antibody directed against complement factor D (CFD), is designed to treat geographic atrophy (GA) secondary to age-related macular degeneration. Given the lack of clinical efficacy observed in patients with GA in the phase...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Ophthalmology Science |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666914523000180 |
| _version_ | 1797671400884928512 |
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| author | Rose Edmonds, MS Verena Steffen, MSc Lee A. Honigberg, PhD Michael C. Chang, PhD |
| author_facet | Rose Edmonds, MS Verena Steffen, MSc Lee A. Honigberg, PhD Michael C. Chang, PhD |
| author_sort | Rose Edmonds, MS |
| collection | DOAJ |
| description | Purpose: Lampalizumab, an antigen-binding fragment of a humanized monoclonal antibody directed against complement factor D (CFD), is designed to treat geographic atrophy (GA) secondary to age-related macular degeneration. Given the lack of clinical efficacy observed in patients with GA in the phase III Chroma/Spectri trials, we investigated the impact of lampalizumab on the complement system in vivo. We developed 6 novel assays to measure changes in complement pathway activities in aqueous humor samples collected from patients enrolled in these trials. Design: Chroma/Spectri were double-masked, sham-controlled, 96-week trials. Participants: Aqueous humor samples from 97 patients with bilateral GA across all groups (i.e., intravitreous lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested. Methods: Novel antibody capture assays were developed on the Simoa platform for complement factor B (CFB), the Bb fragment of CFB, intact complement component 3 (C3), processed C3, intact complement component 4 (C4), and processed C4. Main Outcome Measures: The ratio of processed vs. intact complement factors (i.e., complement activity) in aqueous humor were assessed. Results: Patients treated with either of the lampalizumab regimens demonstrated an increase in CFD level at week 24 compared with baseline, along with a corresponding median reduction in the Bb:CFB ratio of 41% to 43%. There were no strong correlations between lampalizumab concentrations in aqueous humor and change in CFD levels or Bb:CFB ratio over time. No change in downstream C3 processing was observed with lampalizumab treatment. Additionally, there was no change in C4 processing. Conclusions: The collection of aqueous humor samples from patients in Chroma and Spectri trials provided key insights on the effects of lampalizumab, a novel complement inhibitor, on local ocular complement activation. Lampalizumab inhibited the alternative complement pathway in the eyes of patients with GA; however, this did not translate into a measurable reduction in either classical or total complement activity, based on absence of changes in C4 and C3 processing, respectively. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. |
| first_indexed | 2024-03-11T21:14:59Z |
| format | Article |
| id | doaj.art-77ee63aa587c4d2c901652e1beaa3098 |
| institution | Directory Open Access Journal |
| issn | 2666-9145 |
| language | English |
| last_indexed | 2024-03-11T21:14:59Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ophthalmology Science |
| spelling | doaj.art-77ee63aa587c4d2c901652e1beaa30982023-09-29T04:45:18ZengElsevierOphthalmology Science2666-91452023-09-0133100286Alternative Complement Pathway Inhibition by LampalizumabRose Edmonds, MS0Verena Steffen, MSc1Lee A. Honigberg, PhD2Michael C. Chang, PhD3Department of OMNI Biomarker Development, Genentech, Inc., South San Francisco, CaliforniaDepartment of Biostatistics, Genentech, Inc., South San Francisco, CaliforniaDepartment of OMNI Biomarker Development, Genentech, Inc., South San Francisco, CaliforniaDepartment of OMNI Biomarker Development, Genentech, Inc., South San Francisco, California; Correspondence: Michael C. Chang, PhD, Department of OMNI Biomarker Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080.Purpose: Lampalizumab, an antigen-binding fragment of a humanized monoclonal antibody directed against complement factor D (CFD), is designed to treat geographic atrophy (GA) secondary to age-related macular degeneration. Given the lack of clinical efficacy observed in patients with GA in the phase III Chroma/Spectri trials, we investigated the impact of lampalizumab on the complement system in vivo. We developed 6 novel assays to measure changes in complement pathway activities in aqueous humor samples collected from patients enrolled in these trials. Design: Chroma/Spectri were double-masked, sham-controlled, 96-week trials. Participants: Aqueous humor samples from 97 patients with bilateral GA across all groups (i.e., intravitreous lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested. Methods: Novel antibody capture assays were developed on the Simoa platform for complement factor B (CFB), the Bb fragment of CFB, intact complement component 3 (C3), processed C3, intact complement component 4 (C4), and processed C4. Main Outcome Measures: The ratio of processed vs. intact complement factors (i.e., complement activity) in aqueous humor were assessed. Results: Patients treated with either of the lampalizumab regimens demonstrated an increase in CFD level at week 24 compared with baseline, along with a corresponding median reduction in the Bb:CFB ratio of 41% to 43%. There were no strong correlations between lampalizumab concentrations in aqueous humor and change in CFD levels or Bb:CFB ratio over time. No change in downstream C3 processing was observed with lampalizumab treatment. Additionally, there was no change in C4 processing. Conclusions: The collection of aqueous humor samples from patients in Chroma and Spectri trials provided key insights on the effects of lampalizumab, a novel complement inhibitor, on local ocular complement activation. Lampalizumab inhibited the alternative complement pathway in the eyes of patients with GA; however, this did not translate into a measurable reduction in either classical or total complement activity, based on absence of changes in C4 and C3 processing, respectively. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.http://www.sciencedirect.com/science/article/pii/S2666914523000180Alternative complement pathwayLampalizumabChroma and Spectri trialsGeographic atrophyAntibody conjugate assay |
| spellingShingle | Rose Edmonds, MS Verena Steffen, MSc Lee A. Honigberg, PhD Michael C. Chang, PhD Alternative Complement Pathway Inhibition by Lampalizumab Ophthalmology Science Alternative complement pathway Lampalizumab Chroma and Spectri trials Geographic atrophy Antibody conjugate assay |
| title | Alternative Complement Pathway Inhibition by Lampalizumab |
| title_full | Alternative Complement Pathway Inhibition by Lampalizumab |
| title_fullStr | Alternative Complement Pathway Inhibition by Lampalizumab |
| title_full_unstemmed | Alternative Complement Pathway Inhibition by Lampalizumab |
| title_short | Alternative Complement Pathway Inhibition by Lampalizumab |
| title_sort | alternative complement pathway inhibition by lampalizumab |
| topic | Alternative complement pathway Lampalizumab Chroma and Spectri trials Geographic atrophy Antibody conjugate assay |
| url | http://www.sciencedirect.com/science/article/pii/S2666914523000180 |
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