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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 -
Immunotherapy Feb 2018We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti-CD38) monotherapy...
We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti-CD38) monotherapy achieved overall response (OR) of 24%. Other monoclonal antibodies that have shown efficacy in combination therapy include siltuximab (OR: 66%), indatuximab (OR: 78%), isatuximab (OR: 64.5%), pembrolizumab (OR: 60%), bevacizumab (OR: 70%), dacetuzumab (OR: 39%) and lorvotuzumab (OR: 56.4%). No OR was observed with monotherapy using BI-505, siltuximab, bevacizumab, AVE-1642, figitumumab, atacicept, milatuzumab, dacetuzumab, lucatumumab, IPH2101, lorvotuzumab, BT062 and nivolumab. We included seven clinical trials on chimeric antigen receptor (CAR) T cells. CAR T-cell targets include BCMA, CD19, KLC and CD138. A recent experience of CAR T-cell (B-cell maturation antigen) therapy in advanced MM has shown global response of 100%. The future of monoclonal antibodies and adoptive T cells for MM treatment seems promising.
Topics: Humans; Immunotherapy; Multiple Myeloma
PubMed: 29421983
DOI: 10.2217/imt-2017-0136 -
British Journal of Haematology Jul 2018
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents, Immunological; Female; Frail Elderly; Histocompatibility Antigens Class II; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Patient-Centered Care; Quality of Life
PubMed: 28466956
DOI: 10.1111/bjh.14726 -
Drugs of Today (Barcelona, Spain : 1998) Jun 2016The 2016 Annual European Congress of Rheumatology, an annual conference organized by the European League Against Rheumatism (EULAR), took place in London, U.K. Over...
The 2016 Annual European Congress of Rheumatology, an annual conference organized by the European League Against Rheumatism (EULAR), took place in London, U.K. Over 4,000 abstracts were submitted this year with over 199 sessions and poster tours on offer. The congress has become a major event in the field of rheumatology with participants attending from around the world. The oral sessions, poster displays and lectures cover a broad spectrum of topics, including the latest understanding of disease processes, as well as recent advances in diagnosis and patient care.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Humans; Piperidines; Pyrimidines; Pyrroles; Rheumatic Diseases; Rheumatology
PubMed: 27458612
DOI: 10.1358/dot.2016.52.6.2516435 -
Expert Opinion on Emerging Drugs Jun 2016Monoclonal antibodies mark the beginning of a new era in the context of multiple myeloma (MM) treatment. Numerous antibodies have been tested or are currently in... (Review)
Review
INTRODUCTION
Monoclonal antibodies mark the beginning of a new era in the context of multiple myeloma (MM) treatment. Numerous antibodies have been tested or are currently in development for patients with MM, in order to improve tolerability and quality of life.
AREAS COVERED
This manuscript reviews emerging antibodies for the treatment of MM i.e. elotuzumab, daratumumab, MOR03087, isatuximab, bevacizumab, cetuximab, siltuximab, tocilizumab, elsilimomab, azintrel, rituximab, tositumomab, milatuzumab, lucatumumab, dacetuzumab, figitumumab, dalotuzumab, AVE1642, tabalumab, pembrolizumab, pidilizumab, nivolumab.
EXPERT OPINION
Amongst these antibodies, elotuzumab which targets SLAMF-7 and daratumumab which targets CD38, have been recently approved by FDA for patients with relapsed/refractory MM. Both agents are well tolerated. Multiple clinical trials incorporating these monoclonal antibodies in MM treatment are currently ongoing. Of special interest are the anticipated results of phase III clinical trials with elotuzumab [NCT0189164; NCT01335399; NCT02495922] and daratumumab [NCT02252172; NCT02195479] in newly diagnosed MM patients. Moreover, of great interest are the awaited data on pembrolizumabin combination with pomalidomide and dexamethasone in refractory/relapsed MM patients [NCT02576977] and in combination with lenalidomide and dexamethasone in newly diagnosed MM patients. It seems that the incorporation of monoclonal antibodies will change the landscape of myeloma therapy in the near future.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Design; Humans; Multiple Myeloma; Quality of Life
PubMed: 27195659
DOI: 10.1080/14728214.2016.1186644 -
BioDrugs : Clinical Immunotherapeutics,... Apr 2016The antibody-drug conjugate (ADC) is a combination of a cytotoxic agent and monoclonal antibodies (mAbs) through a stable specialized chemical linker. After ADC binds to... (Review)
Review
The antibody-drug conjugate (ADC) is a combination of a cytotoxic agent and monoclonal antibodies (mAbs) through a stable specialized chemical linker. After ADC binds to the target antigen, the conjugate is internalized and toxin is released, leading to the death of a target cell. Lorvotuzumab mertansine, indatuximab ravtansine, and milatuzumab-doxorubicin are currently under clinical development for use in multiple myeloma (MM). Preliminary data from recent studies indicate that these agents induce responses in patients with relapsed and/or refractory MM and have an acceptable safety profile.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Immunoconjugates; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 26927803
DOI: 10.1007/s40259-016-0165-6 -
Experimental Hematology Sep 2015Mantle-cell lymphoma (MCL) remains incurable despite numerous therapeutic advances. OSU-2S, a novel nonimmunosuppressive FTY720 (Fingolimod) derivative, exhibits potent...
Mantle-cell lymphoma (MCL) remains incurable despite numerous therapeutic advances. OSU-2S, a novel nonimmunosuppressive FTY720 (Fingolimod) derivative, exhibits potent cytotoxicity in MCL cell lines and primary cells. OSU-2S increased the surface expression of CD74, a therapeutic antibody target in MCL cells. OSU-2S, in combination with anti-CD74 antibody milatuzumab, enhanced cytotoxicity in MCL. Moreover, MCL tumor antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) targeted immunonanoparticle-carrying OSU-2S (2A2-OSU-2S-ILP)-mediated selective cytotoxicity of MCL in vitro, as well as activity in a xenografted mouse model of MCL in vivo. The newly developed OSU-2S delivery using ROR1-directed immunonanoparticles provide selective targeting of OSU-2S to MCL and other ROR1(+) malignancies, sparing normal B cells.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antigens, Differentiation, B-Lymphocyte; Antigens, Neoplasm; Cytotoxins; Drug Delivery Systems; Fingolimod Hydrochloride; Histocompatibility Antigens Class II; Humans; Lymphoma, Mantle-Cell; Mice; Mice, Inbred NOD; Propylene Glycols; Receptor Tyrosine Kinase-like Orphan Receptors; Sphingosine; Xenograft Model Antitumor Assays
PubMed: 25937048
DOI: 10.1016/j.exphem.2015.04.008 -
British Journal of Haematology Jun 2015As a result of the anti-tumour activity observed in vitro and in vivo with combined anti-CD20 and anti-CD74 antibodies, we initiated a phase I/II trial of veltuzumab and...
The combination of milatuzumab, a humanized anti-CD74 antibody, and veltuzumab, a humanized anti-CD20 antibody, demonstrates activity in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.
As a result of the anti-tumour activity observed in vitro and in vivo with combined anti-CD20 and anti-CD74 antibodies, we initiated a phase I/II trial of veltuzumab and milatuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). Patients received an induction of veltuzumab 200 mg/m(2) weekly combined with escalating doses of milatuzumab at 8, 16 and 20 mg/kg weekly for 4 weeks. Patients without disease progression could receive an extended induction with treatment on weeks 12, 20, 28 and 36. A total of 35 patients enrolled on the study. Median age was 63 years, median number of prior therapies was 3, and 63% of patients were rituximab refractory. No dose-limiting toxicities were observed in the phase I study. Related grade 3-4 toxicities included lymphopenia, leucopenia, neutropenia, anaemia, infusion reactions, hyperglycaemia, fatigue and atrial tachycardia. Median weeks of therapy was 12 and 29% of patients completed all 36 weeks of therapy. The overall response rate was 24%, median duration of response was 12 months, and responses were observed at all dose levels and in 50% of patients refractory to rituximab. Combination therapy with veltuzumab and milatuzumab demonstrated activity in a population of heavily pre-treated patients with relapsed or refractory indolent NHL.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Grading; Treatment Outcome
PubMed: 25847298
DOI: 10.1111/bjh.13354