A Phase 1, Double-Blind (Sponsor-Unblinded), Placebo-Controlled, Dose Escalation Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Single And Multiple Doses Of CSL040 In Healthy Adult Subjects

First-In-Human Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Escalating Single And Multiple Doses Of CSL040 In Healthy Subjects

开始日期2023-09-28

申办/合作机构

CSL Behring LLC

100 项与 CSL-040 相关的临床结果

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100 项与 CSL-040 相关的转化医学

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100 项与 CSL-040 相关的专利（医药）

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项与 CSL-040 相关的文献（医药）

2024-07-01·Journal of Biological Chemistry

Mechanistic insights into complement pathway inhibition by CR1 domain duplication

Article

作者: Ewert, Svenja ; Hardy, Matthew P ; Baz Morelli, Adriana ; Rowe, Tony ; Nair, Anup G ; Pelzing, Matthias ; Wan, Soo San ; Powers, Glenn A ; Wymann, Sandra

Complement receptor 1 (CR1) is a membrane glycoprotein with a highly duplicated domain structure able to bind multiple ligands such as C3b and C4b, the activated fragments of complement components C3 and C4, respectively. We have previously used our knowledge of this domain structure to identify CSL040, a soluble extracellular fragment of CR1 containing the long homologous repeat (LHR) domains A, B, and C. CSL040 retains the ability to bind both C3b and C4b but is also a more potent complement inhibitor than other recombinant CR1-based therapeutics. To generate soluble CR1 variants with increased inhibitory potential across all three complement pathways, or variants with activity skewed to specific pathways, we exploited the domain structure of CR1 further by generating LHR domain duplications. We identified LHR-ABCC, a soluble CR1 variant containing a duplicated C3b-binding C-terminal LHR-C domain that exhibited significantly enhanced alternative pathway inhibitory activity in vitro compared to CSL040. Another variant, LHR-BBCC, containing duplications of both LHR-B and LHR-C with four C3b binding sites, was shown to have reduced classical/lectin pathway inhibitory activity compared to CSL040, but comparable alternative pathway activity. Interestingly, multiplication of the C4b-binding LHR-A domain resulted in only minor increases in classical/lectin pathway inhibitory activity. The CR1 duplication variants characterized in these in vitro potency assays, as well as in affinity in solution C3b and C4b binding assays, not only provides an opportunity to identify new therapeutic molecules but also additional mechanistic insights to the multiple interactions between CR1 and C3b/C4b.

2023-10-13·Biomolecules

The Molecular Mechanisms of Complement Receptor 1-It Is Complicated.

Review

作者: Wymann, Sandra ; Rowe, Tony ; Hardy, Matthew P ; Mansour, Mariam

Human complement receptor 1 (CR1) is a membrane-bound regulator of complement that has been the subject of recent attempts to generate soluble therapeutic compounds comprising different fragments of its extracellular domain. This review will focus on the extracellular domain of CR1 and detail how its highly duplicated domains work both separately and together to mediate binding to its main ligands C3b and C4b, and to inhibit the classical, lectin, and alternative pathways of the complement cascade via the mechanisms of decay acceleration activity (DAA) and co-factor activity (CFA). Understanding the molecular basis of CR1 activity is made more complicated by the presence not only of multiple ligand binding domains within CR1 but also the fact that C3b and C4b can interact with CR1 as both monomers, dimers, and heterodimers. Evidence for the interaction of CR1 with additional ligands such as C1q will also be reviewed. Finally, we will bring the mechanistic understanding of CR1 activity together to provide an explanation for the differential complement pathway inhibition recently observed with CSL040, a soluble CR1-based therapeutic candidate in pre-clinical development.

2022-05-13·Biochemical Journal3区 · 生物学

Sialylation-dependent pharmacokinetics and differential complement pathway inhibition are hallmarks of CR1 activityin vivo

3区 · 生物学

Article

作者: Tomasetig, Vesna ; Rowe, Tony ; Powers, Glenn A. ; Mischnik, Marcel ; Halder, Partho ; Tan, Xiahui ; Owczarek, Catherine M. ; Hardy, Matthew P. ; Ghosh, Subhajit ; Wymann, Sandra ; Dower, Steven K. ; Ow, Saw Yen ; Kuehnemuth, Benjamin ; Rossato, Paolo ; Cao, Helen ; de Souza, Mitchell J. ; Baz Morelli, Adriana ; James, Hannah S. ; Leong, David ; Lind, Holger

Human Complement Receptor 1 (HuCR1) is a potent membrane-bound regulator of complement both in vitro and in vivo, acting via interaction with its ligands C3b and C4b. Soluble versions of HuCR1 have been described such as TP10, the recombinant full-length extracellular domain, and more recently CSL040, a truncated version lacking the C-terminal long homologous repeat domain D (LHR-D). However, the role of N-linked glycosylation in determining its pharmacokinetic (PK) and pharmacodynamic (PD) properties is only partly understood. We demonstrated a relationship between the asialo-N-glycan levels of CSL040 and its PK/PD properties in rats and non-human primates (NHPs), using recombinant CSL040 preparations with varying asialo-N-glycan levels. The clearance mechanism likely involves the asialoglycoprotein receptor (ASGR), as clearance of CSL040 with a high proportion of asialo-N-glycans was attenuated in vivo by co-administration of rats with asialofetuin, which saturates the ASGR. Biodistribution studies also showed CSL040 localization to the liver following systemic administration. Our studies uncovered differential PD effects by CSL040 on complement pathways, with extended inhibition in both rats and NHPs of the alternative pathway compared with the classical and lectin pathways that were not correlated with its PK profile. Further studies showed that this effect was dose dependent and observed with both CSL040 and the full-length extracellular domain of HuCR1. Taken together, our data suggests that sialylation optimization is an important consideration for developing HuCR1-based therapeutic candidates such as CSL040 with improved PK properties and shows that CSL040 has superior PK/PD responses compared with full-length soluble HuCR1.

100 项与 CSL-040 相关的药物交易

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