An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA

Area of Science:

• Transplant immunology
• Complement system biology
• Immunopathology

Background:

• Antibody-mediated rejection (AMR) in solid organ transplants (SOT) involves donor-specific antibodies (DSA) targeting human leukocyte antigens (HLA).
• The Fc region of DSA activates the complement cascade, leading to inflammation and tissue damage, key features of AMR.
• Complement activation contributes significantly to the pathology of AMR following transplantation.

Purpose of the Study:

• To investigate the efficacy of TNT003, an anti-C1s monoclonal antibody, in inhibiting complement activation induced by HLA antibodies (HLA-Ab).
• To evaluate TNT003's potential in mitigating complement-mediated damage in the context of AMR.

Main Methods:

• Novel cell- and bead-based assays were developed to assess complement deposition.
• Human aortic endothelial cells (HAEC) were treated with HLA-Ab and human complement to measure activated complement proteins via flow cytometry.
• C3d deposition on single antigen beads (SAB) incubated with HLA-Ab and complement was quantified.

Main Results:

• TNT003 demonstrated a concentration-dependent inhibition of HLA-Ab-mediated complement deposition on HAEC.
• Production of complement split products (C3a, C4a, C5a) was significantly reduced by TNT003.
• TNT003 effectively blocked C3d deposition induced by both HLA Class I and Class II specific antibodies on SAB.

Conclusions:

• TNT003 inhibits complement deposition and anaphylatoxin formation triggered by HLA antibodies in vitro.
• These findings suggest TNT003 holds potential for modulating the detrimental effects of DSA in AMR.
• Targeting C1s with TNT003 offers a promising strategy for managing complement-mediated transplant rejection.