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2091 Discovery of JNJ-67856633: A Novel, First-in-Class MALT1 Protease Inhibitor for the Treatment of B Cell Lymphomas

Program: Oral and Poster Abstracts
Session: 625. Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster II
Hematology Disease Topics & Pathways:
Diseases, Non-Biological, Therapies, chemical interactions, DLBCL, B-Cell Lymphoma, Lymphoid Malignancies, pharmacology
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Ulrike Philippar, PhD1, Ricardo M. Attar, PhD2, Tianbao Lu3*, Lorena Fontan, PhD4, Nele Vloemans1*, Mariette Bekkers1*, Luc Van Nuffel1*, Marcello Gaudiano5*, Katarzyna Wnuk-Lipinska, PhD5*, Bas-jan Van Der Leede1*, Katie Amssoms1*, Kristof Kimpe1*, Bart Medaer1*, Tony Greway3*, Yann Abraham, PhD6*, Max Cummings3*, Emanuele Trella1*, Greet Vanhoof1*, Weimei Sun7*, Jan Willem Thuring1*, Peter Connolly3*, Joannes Linders, PhD1*, Haopeng Rui8*, Sriram Balasubramanian9, John Gerecitano, MD, PhD10, Jenna D. Goldberg, MD11*, Ari Melnick, MD12, Yusri A Elsayed, MD, PhD13*, Jennifer Smit11*, Jacqueline Bussolari, PhD14 and James P Edwards15*

1Janssen Research & Development, Beerse, Belgium
2Janssen Research & Development, L.L.C., Spring House, PA
3Janssen Research & Development, Springhouse
4Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Long Island City, NY
5Janssen Research & Development, Beerse, BEL
6Computational Sciences, Janssen R&D, Beerse, Belgium
7Johnson & Johnson PRD, Spring House, PA
8Janssen Research & Development, Shanghai, China
9Janssen R&D, La Jolla, CA
10The Janssen Pharmaceutical Companies of Johnson & Johnson, West New York, NJ
11Janssen R&D, Raritan, NJ
12Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY
13Janssen R&D, Spring House, PA
14Janssen Research & Development, LLC, Raritan, NJ
15Janssen Research & Development, La Jolla


Constitutive activation of the classical nuclear factor kappa-light-chain-enhancer of activated B‑cells (NF‑κB) pathway is a clear driver of B‑cell lymphomas, especially the aggressive activated B‑cell (ABC) subtype of diffuse large B‑cell lymphoma (DLBCL). Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key mediator of the classical NF-κB signaling pathway downstream of B-cell receptor and T-cell receptor. MALT1 possesses 2 functions: a scaffolding function to recruit NF-κB signaling proteins and a protease function to cleave and inactivate inhibitors of the NF-κB signaling pathway.


Using a high-throughput screen followed by iterative structure-activity relationship (SAR) analyses, the MALT1 inhibitor JNJ-67856633 was identified. JNJ-67856633 was evaluated using biochemical, cellular in vitro, in vivo tumor efficacy and safety models.


JNJ-67856633 is a potent, selective, allosteric inhibitor of MALT1 protease activity as measured by biochemical assays or downstream cellular cytokine readouts (IL6/10) or direct MALT1 substrate cleavage (RelB, BCL10). The compound inhibits proliferation of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines bearing CD79b or CARD11 mutations as well as models mimicking resistance to covalent Bruton’s Tyrosine Kinase (BTK) inhibitors. Furthermore, combination effects were observed in CD79b cellular ABC-DLBCL models when JNJ-67856633 was combined with a BTK inhibitor. JNJ-67856633 showed activity in organoid cultures derived from ABC-DLBCL patients. JNJ-67856633 leads to potent in vivo pharmacodynamic shutdown in CD79b- as well as CARD11-mutant ABC-DLBCL models as measured by serum IL10 or uncleaved BCL10 levels in tumors. JNJ-67856633 exhibits potent tumor growth inhibition in two human DLBCL xenograft models, OCI Ly3 and OCI Ly10. In addition, >5 patient derived DLBCL xenografts were evaluated and activity in mutation selected models was observed.

To address the role of MALT1 inhibition in T cells, primary human T cells derived from normal healthy volunteers were treated with JNJ-67856633 in vitro. Dose dependent inhibition of the generation of Tregs (CD4+CD25+FoxP3+) following CD3/28 stimulation was observed upon treatment with JNJ-67856633 suggesting a potential immune modulatory role of MALT1 inhibition.


Phase 1 clinical trials assessing the safety and efficacy of JNJ-67856633 initiated in 2019. JNJ-67856633 is a combination partner for BTK inhibitors and a promising treatment option for BTKi-resistant tumors, with demonstrated preclinical activity in CARD11 mutant tumors. In addition to ABC-DLBCL, a MALT1 inhibitor is a promising treatment option for patients with CLL, MCL, WM, and FL whose tumors have been shown to be sensitive to inhibition of BTK. MALT lymphomas, characterized by MALT1 and BCL10 translocation, represent another attractive target for MALT1 inhibition.

Disclosures: Philippar: Johnson & Johnson: Current Employment. Attar: Johnson & Johnson: Current Employment. Lu: Johnson & Johnson: Current Employment. Fontan: Johnson & Johnson: Current Employment. Vloemans: Johnson & Johnson: Current Employment. Bekkers: Johnson & Johnson: Current Employment. Van Nuffel: Johnson & Johnson: Ended employment in the past 24 months. Gaudiano: Johnson & Johnson: Current Employment. Wnuk-Lipinska: Johnson & Johnson: Ended employment in the past 24 months. Van Der Leede: Johnson & Johnson: Current Employment. Amssoms: Johnson & Johnson: Current Employment. Kimpe: Johnson & Johnson: Current Employment. Medaer: Johnson & Johnson: Current Employment. Greway: Johnson & Johnson: Current Employment. Abraham: Johnson & Johnson: Current Employment. Cummings: Johnson & Johnson: Ended employment in the past 24 months. Trella: Johnson & Johnson: Current Employment. Vanhoof: Johnson & Johnson: Current Employment. Sun: Johnson & Johnson: Current Employment. Thuring: Johnson & Johnson: Current Employment. Connolly: Johnson & Johnson: Current Employment. Linders: Johnson & Johnson: Current Employment. Rui: Johnson & Johnson: Current Employment. Balasubramanian: Johnson & Johnson: Current Employment. Gerecitano: Janssen: Current Employment. Goldberg: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Melnick: Janssen: Research Funding; Epizyme: Consultancy; Daiichi Sankyo: Research Funding; Constellation: Consultancy; Jubilant: Consultancy. Elsayed: Johnson & Johnson: Current Employment. Smit: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Bussolari: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Edwards: Johnson & Johnson: Current Employment.

*signifies non-member of ASH