Neutralization of BAFF and APRIL with engineered soluble BCMA decoy receptor for the treatment of B-cell malignancies

Thesis

B-cell activation factor (BAFF) and A proliferation-inducing ligand (APRIL), two cytokines regulating B-cell homeostasis, are known to play important roles in the pathogenesis of B-cell malignancies. In B-cell malignancies, significant up-regulation and receptor-mediated signalling of BAFF and APRIL have been shown to facilitate tumour proliferation, treatment-resistance, and contribute to immune suppression in the tumour microenvironment (TME). Multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) are two of the most prevalent types of B-cell malignancies. Despite recent approvals of novel therapeutics such as CAR T-cell therapy (CAR T), disease relapse and treatment resistance continue to pose clinical challenges, often resulting in patient mortality. Here, we found elevated expression levels of BAFF, APRIL and their receptors, and observed the resulting activation of critical survival signalling pathways in patient specimens of MM and DLBCL. To effectively neutralize BAFF and APRIL-mediated signalling, we adopted a ligand trap approach, and developed a decoy receptor by fusing the extracellular cysteine rich domain (ECD) of the BCMA (B-cell maturation antigen) receptor (soluble BCMA, or sBCMA) with a human IgG1 Fc domain, to initially test our hypothesis. Next, to enhance the therapeutic efficacy of the approach, we engineered a mutant sBCMA, and developed a second-generation Fc fusion protein with significantly increased binding affinities toward BAFF and APRIL. In vitro and in vivo studies demonstrated that our sBCMA-Fc ligand trap approach is efficacious at inhibiting tumour growth with minimal off-target normal tissue toxicities, providing preclinical evidence to support the use of our molecules as a treatment for MM and DLBCL.

Authors: Zhang, XE

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: BAFF; soluble receptor; multiple myeloma; decoy receptor; APRIL; lymphoma; ligand trap
• Subjects: Protein drugs; Protein binding; Protein-protein interactions; Hematological oncology; Pharmaceutical biotechnology; Protein engineering