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Experimental Hematology & Oncology Sep 2023Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma subtype which remains incurable despite multimodal approach including chemoimmunotherapy followed by...
BACKGROUND
Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma subtype which remains incurable despite multimodal approach including chemoimmunotherapy followed by stem cell transplant, targeted approaches such as the BTK inhibitor ibrutinib, and CD19 chimeric antigen receptor (CAR) T cells. CD74 is a nonpolymorphic type II integral membrane glycoprotein identified as an MHC class II chaperone and a receptor for macrophage migration inhibitory factor. Our group previously reported on CD74's abundant expression in MCL and its ability to increase via pharmacological inhibition of autophagosomal degradation. Milatuzumab, a fully humanized anti-CD74 monoclonal antibody, demonstrated significant activity in preclinical lymphoma models but failed to provide meaningful benefits in clinical trials mainly due to its short half-life. We hypothesized that targeting CD74 using a CAR-T cell would provide potent and durable anti-MCL activity.
METHODS
We engineered a second generation anti-CD74 CAR with 4-1BB and CD3ζ signaling domains (74bbz). Through in silico and rational mutagenesis on the scFV domain, the 74bbz CAR was functionally optimized for superior antigen binding affinity, proliferative signaling, and cytotoxic activity against MCL cells in vitro and in vivo.
RESULTS
Functionally optimized 74bbz CAR-T cells (clone 42105) induced significant killing of MCL cell lines, and primary MCL patient samples including one relapse after commercial CD19 CAR-T cell therapy with direct correlation between antigen density and cytotoxicity. It significantly prolonged the survival of an animal model established in NOD-SCIDγc (NSG) mice engrafted with a human MCL cell line Mino subcutaneously compared to controls. Finally, while CD74 is also expressed on normal immune cell subsets, treatment with 74bbz CAR-T cells resulted in minimal cytotoxicity against these cells both in vitro and in vivo.
CONCLUSIONS
Targeting CD74 with 74bbz CAR-T cells represents a new cell therapy to provide a potent and durable and anti-MCL activity.
PubMed: 37740214
DOI: 10.1186/s40164-023-00437-8 -
European Journal of Medicinal Chemistry Dec 2022The iron-dependent, non-apoptotic cell death, known as ferroptosis is an emerging strategy for the development of anticancer drugs. RSL3 was identified as an activator...
The iron-dependent, non-apoptotic cell death, known as ferroptosis is an emerging strategy for the development of anticancer drugs. RSL3 was identified as an activator of ferroptosis through the inhibition of the glutathione peroxidase 4 (GPX4) which plays a crucial role in the cellular lipid oxidative stress. RSL3 is characterized by the presence of an electrophilic chloroacetyl moiety, namely warhead which covalently bonds to the catalytic and nucleophilic selenocysteine residue (Sec46) of GPX4. Like the major ferroptosis inducers, RSL3 suffers from lack of selectivity toward tumor cells. In this study, we report the first synthesis of an antibody-drug conjugate (ADC) containing RSL3 fragment and trastuzumab with the aim to deliver the agent selectively to tumors. The synthesis uses a judiciously chosen strategy to preserve the vital but fragile warhead. Full characterization of the ADC was accomplished, demonstrating the generation of a homogeneous DAR 8 conjugate. The robustness of the synthesis was successfully applied to another ADC associating the anti-CD74 mAb milatuzumab. The ADC induces ferroptotic cell death through reactive oxygen species accumulation and increases the activity of doxorubicin. The ADC associating trastuzumab and RSL3 may therefore offer potential applications in vectorized therapy alone or in combination with conventional chemotherapies.
Topics: Ferroptosis; Immunoconjugates; Lipid Peroxidation; Carbolines; Trastuzumab
PubMed: 36334452
DOI: 10.1016/j.ejmech.2022.114863 -
Annals of the Rheumatic Diseases Jul 2021
Randomized Controlled Trial
Topics: Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Double-Blind Method; Histocompatibility Antigens Class II; Humans; Intramolecular Oxidoreductases; Lupus Erythematosus, Systemic; Macrophage Migration-Inhibitory Factors
PubMed: 33619162
DOI: 10.1136/annrheumdis-2020-219803