Lee, LSH; (2017) APRIL based therapeutic strategies to target BCMA and TACI in multiple myeloma. Doctoral thesis , UCL (University College London).

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Abstract

Myeloma remains largely incurable and there is an unmet need for new therapies. B-cell maturation antigen(BCMA) is an attractive therapeutic target due to its restricted expression on normal and malignant plasma cells(PC). A natural ligand for BCMA is a proliferating ligand(APRIL) which also naturally binds another antigen expressed on myeloma cells: Transmembrane activator and CAML interactor(TACI). APRIL is an attractive binder as it is a compact, self-protein which binds both BCMA and TACI with high affinity. BCMA and TACI expression was quantified on tumour cells from a large number of patients to explore the clinical utility of targeting these antigens. Tumour BCMA expression was found in all patients, persisted with relapse and extramedullary spread and low levels was associated with improved patient outcome. However BCMA expression was variable, often low and TACI was co-expressed on tumour from 78% of patients. Recognising that dual antigen targeting of BCMA and TACI may increase target antigens on tumour and reduce the risk of antigen negative disease escape, an APRIL based chimeric antigen receptor(ACAR) was optimised and in vitro activity against BCMA and TACI targets demonstrated. Target kill was seen at low levels of antigen and low effector to target ratios and further, potent ACAR efficacy was demonstrated in vivo in an intramedullary murine myeloma model. A targeted mutagenesis strategy was also used to generate a BCMA specific APRIL mutant. When APRIL mutant was used in a CAR(ACAR-mut), specificity was confirmed for BCMA targets, however there was no significant T cell expansion against primary tumour. In a second strategy, APRIL based bispecific molecules were engineered consisting of a CD3 specific single chain variable fragment linked to an APRILWT(APRILiTE). Preliminary studies using unpurified and unquantified protein in co-cultures of target and activated T cells, demonstrated cytolysis of BCMA expressing cells and primary myeloma cells using APRILiTE. Therefore, APRIL based therapeutic strategies provide a novel and promising approach to immunotherapy in myeloma.

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