Abstract 832P
Background
MALT1 plays a key role in antigen receptor signalling and preclinical data indicate that MALT1 protease inhibition may have benefit in tumours with dysregulated NF-κB signalling, including activated B-cell-diffuse large B-cell lymphoma (ABC-DLBCL). MALT1 inhibitors are in clinical development as monotherapies and in combination with other agnets for the treatment of oncology and haematology indications, including lymphoma.
Methods
EXS73565 (‘565) was designed using generative design, machine learning and molecular dynamics approaches. The compound was characterised in MALT1 protease assays and DLBCL functional studies. In vivo efficacy of ‘565 was assessed in mouse xenograft models, alone and in combination with the BTK inhibitor ibrutinib. Profiling of ‘565 was undertaken in a range of selectivity and preclinical studies.
Results
‘565 is a potent and selective allosteric inhibitor of the MALT1 protease and inhibits the production of IL-10 and proliferation of DLBCL cells. In ABC-DLBCL xenograft studies, ‘565 demonstrated significant tumour growth inhibition. Tumour target engagement was demonstrated through measurement of the MALT1 protease target, RelB, and effects on NF-κB target genes. In an ABC-DLBCL xenograft model with low sensitivity to single-agent MALT1 and BTK inhibition in vivo, combining ‘565 and ibrutinib provided significant synergistic efficacy. Evaluation of ‘565 showed limited activity against CYP450 enzymes, hepatic and renal transporters. Notably, ‘565 avoids inhibition of UGT1A1 (an enzyme involved in metabolising bilirubin and certain small molecule drugs) in comparison to some clinical stage MALT1 inhibitors which carry a high UGT1A1 inhibition risk.
Conclusions
We describe the characterisation of EXS73565, an allosteric inhibitor of MALT1 which is currently in IND/CTA-enabling studies. Importantly, we show that ‘565 exhibits a low drug-drug interaction and hyperbilirubinemia risk, offering the prospect of fully exploring the potential of MALT1 inhibition as a monotherapy and/or in combination with other targeted agents.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Exscientia.
Disclosure
M. Gooyit, S. Varzandeh, A. Gavard, S. Robinson, F. Breitgoff, A. Cooke, A. Bradley, M. Dominguez: Financial Interests, Personal, Stocks/Shares: Exscientia; Other, Personal, Full or part-time Employment: Exscientia. A. Payne: Financial Interests, Personal, Stocks/Shares: Exscientia; Non-Financial Interests, Personal, Full or part-time Employment: Exscientia. C. Carvalheda, D. Evans, S. Richards, P. Ray: Other, Personal, Full or part-time Employment: Exscientia. C. Radoux, J. Besnard: Other, Personal, Full or part-time Employment: Exscientia; Financial Interests, Personal, Stocks/Shares: Exscientia.
Resources from the same session
833P - New targets for adult T cell leukemia/lymphoma (ATLL): A map for ATLL immunotherapy
Presenter: Zahra Rezaei Borojerdi
Session: Poster session 18
834P - Phase II clinical study of VR-CAP regimen for first-line treatment of marginal zone lymphoma
Presenter: Junfeng Chu
Session: Poster session 18
835P - A safe and effective immunochemotherapy with oral sobuzoxane and etoposide for untreated diffuse large B cell lymphoma patients aged 80 and over
Presenter: Kaname Miyashita
Session: Poster session 18
838P - Matching-adjusted indirect comparison (MAIC) of axicabtagene ciloleucel (axi-cel) and epcoritamab (epcor) in relapsed/refractory (R/R) large B cell lymphoma (LBCL) after at least two prior systemic therapies (3L+)
Presenter: Olalekan Oluwole
Session: Poster session 18
840P - Genomic landscape, immune characteristics and prognostic mutation signature of extranodal NK/T cell lymphoma, nasal type in China
Presenter: Yue Chai
Session: Poster session 18
841P - Ki67-revised risk index to risk-stratify patients with extra-nodal natural killer/T cell lymphoma
Presenter: Shuo Li
Session: Poster session 18
842P - Multicenter real-world study of newly diagnosed advanced-stage extranodal natural killer/T cell lymphoma (ENKTL): Proposal for intensive therapy
Presenter: Yu-Ce Wei
Session: Poster session 18