Anti-CD37 α-amanitin–conjugated antibodies as potential therapeutic weapons for Richter syndrome

Vaisitti, Tiziana; Vitale, Nicoletta; Micillo, Matilde; Brandimarte, Lorenzo; Iannello, Andrea; Papotti, M; Jakšić, Ozren; Lopez, Gianluca; Napoli, Arianna Di; Cutrìn, Juan Carlos; Orlik, Christian; Kulke, Michael; Pahl, Andreas; Deaglio, Silvia

doi:10.1182/blood.2022016211

Cited by 9 publications

(6 citation statements)

References 26 publications

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“…The payloads of current FDA-approved ADCs include anti-mitotic agents such as monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF) and the maytansine derivatives DM1 and DM4, DNA-damaging agents such as calicheamicins and pyrrolobenzodiazepine dimers (PBDs) and topoisomerase I inhibitors such as SN-38 and DXd. ADCs with other payloads including tubulysins (anti-mitotics) [35][36][37][38][39] , duocarmycins (DNA alkylators) 40 , PNU-159682 (a topoisomerase II inhibitor) [41][42][43] and amanitin (an RNA polymerase II inhibitor) [44][45][46] are currently being evaluated in preclinical and clinical studies. Beyond these cytotoxic payloads, immunomodulators 47 and protein-degrader-recruiting molecules 48 have emerged as promising novel payloads.…”

Section: Payloadsmentioning

confidence: 99%

Exploring the next generation of antibody–drug conjugates

Tsuchikama,

Anami,

et al. 2024

Nat Rev Clin Oncol

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Antibody-drug conjugates (ADCs) are a promising cancer treatment modality that enables the selective delivery of highly cytotoxic payloads to tumours. However, realizing the full potential of this platform necessitates innovative molecular designs to tackle several clinical challenges such as drug resistance, tumour heterogeneity and treatment-related adverse effects. Several emerging ADC formats exist, including bispecific ADCs, conditionally active ADCs (also known as probody-drug conjugates), immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs, and each offers unique capabilities for tackling these various challenges. For example, probody-drug conjugates can enhance tumour specificity, whereas bispecific ADCs and dual-drug ADCs can address resistance and heterogeneity with enhanced activity. The incorporation of immune-stimulating and protein-degrader ADCs, which have distinct mechanisms of action, into existing treatment strategies could enable multimodal cancer treatment. Despite the promising outlook, the importance of patient stratification and biomarker identification cannot be overstated for these emerging ADCs, as these factors are crucial to identify patients who are most likely to derive benefit. As we continue to deepen our understanding of tumour biology and refine ADC design, we will edge closer to developing truly effective and safe ADCs for patients with treatment-refractory cancers. In this Review, we highlight advances in each ADC component (the monoclonal antibody, payload, linker and conjugation chemistry) and provide more-detailed discussions on selected examples of emerging novel ADCs of each format, enabled by engineering of one or more of these components.• To address these challenges, several novel ADC formats have been developed, including bispecific ADCs, probody-drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs.• Probody-drug conjugates are expected to have improved tumour specificity, whereas bispecific ADCs and dual-drug ADCs have the potential to combat drug resistance and tumour heterogeneity.• Integrating immune-stimulating ADCs and protein-degrader ADCs with current treatment regimens might enable multimodal treatment, potentially through several distinct mechanisms of action.• Patient stratification and biomarker identification will be crucial to maximize the clinical benefits of these emerging ADCs.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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Section: Payloadsmentioning

confidence: 99%

Exploring the next generation of antibody–drug conjugates

Tsuchikama,

Anami,

et al. 2024

Nat Rev Clin Oncol

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Section: Drug Conjugated Antibodiesmentioning

confidence: 99%

“…Initial results have come from the use of anti-CD37 mAbs conjugated with the RNA polymerase II inhibitor α-amanitin (amanitin-based ADCs, ATACs) in murine PDX models [135]. CD37 is a surface molecule belonging to the tetraspanin superfamily, selectively highly expressed by normal human B cells, as well as CLL and DLBCL-type RS cells [135,136]. The release of α-amanitin inside the target cells allows the selective fulfillment of its cytotoxic function, interrupting cellular transcription and causing the death of RS cells [135].…”

Section: Drug Conjugated Antibodiesmentioning

confidence: 99%

“…CD37 is a surface molecule belonging to the tetraspanin superfamily, selectively highly expressed by normal human B cells, as well as CLL and DLBCL-type RS cells [135,136]. The release of α-amanitin inside the target cells allows the selective fulfillment of its cytotoxic function, interrupting cellular transcription and causing the death of RS cells [135]. Since their efficacy has been tested only in preclinical studies, there is the need for the start of clinical trials with anti-CD37 ATACs in DLBCL-type RS.…”

Section: Drug Conjugated Antibodiesmentioning

confidence: 99%

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Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy

Mahmoud

Gaïdano

Mouhssine

2023

Cancers

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Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in patients with a previous or simultaneous diagnosis of chronic lymphocytic leukemia (CLL). Two pathological variants of RS are recognized: diffuse large B-cell lymphoma (DLBCL)-type and Hodgkin lymphoma (HL)-type RS. Different molecular mechanisms may explain the pathogenesis of DLBCL-type RS, including genetic lesions, modifications of immune regulators, and B cell receptor (BCR) pathway hyperactivation. Limited data are available for HL-type RS, and its development has been reported to be similar to de novo HL. In this review, we focus on the immune-related pathogenesis and immune system dysfunction of RS, which are linked to BCR over-reactivity, altered function of the immune system due to the underlying CLL, and specific features of the RS tumor microenvironment. The standard of care of this disease consists in chemoimmunotherapy, eventually followed by stem cell transplantation, but limited possibilities are offered to chemo-resistant patients, who represent the majority of RS cases. In order to address this unmet clinical need, several immunotherapeutic approaches have been developed, namely T cell engagement obtained with bispecific antibodies, PD-1/PD-L1 immune checkpoint blockade by the use of monoclonal antibodies, selective drug delivery with antibody-drug conjugates, and targeting malignant cells with anti-CD19 chimeric antigen receptor-T cells.

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“… 16 We have analyzed the role of novel antibody drug conjugates targeting RS using tumor-specific antigens, such as ROR1, 17 or B-cell restricted targets, such as CD37. 18 We have also studied the effects of novel drug combinations, highlighting a synergy between the dual phosphoinositide 3-kinase γ/δ inhibitor duvelisib and BCL-2i. 19 Even though safety issues on the use of duvelisib have limited initial enthusiasm toward the drug, PI3Ki are being evaluated in different combinations in clinical trials for patients with RS (see clinical trials NCT03534323 and NCT03884998).…”

Section: Introductionmentioning

confidence: 99%

A molecular circuit linking the BCR to the NAD biosynthetic enzyme NAMPT is an actionable target in Richter syndrome

Messana,

Fascì,

Vitale

et al. 2024

Blood Advances

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This works defines for the first time a molecular circuit connecting NAMPT activity to the B cell receptor (BCR) pathway. Using four distinct Richter's syndrome patient-derived xenograft models (RS-PDX), we show that B cell receptor cross-linking results in transcriptional activation of the NAD-biosynthetic enzyme nicotinamide mononucleoside phosphoribosyl transferase (NAMPT), with increased protein expression, in turn positively affecting global cellular NAD levels and sirtuins activity. NAMPT blockade, by using the novel OT-82 inhibitor in combination with either BTK or PI3K inhibitors (BTKi or PI3Ki), induces rapid and potent apoptotic responses in all four models, independently of their mutational profile and of the expression of the other NAD biosynthetic enzymes, including nicotinate phosphoribosyltransferase (NAPRT). The connecting link in the circuit is represented by AKT, which is both tyrosine- and serine-phosphorylated by PI3K and deacetylated by sirtuin 1 and 2 to obtain full kinase activation. Acetylation (i.e., inhibition) of AKT following OT-82 administration was shown by 2D gel electrophoresis and immunoprecipitation. Consistently, pharmacological inhibition or silencing of sirtuin 1 and 2 impairs AKT activation and induces apoptosis of RS cells in combination with PI3Ki or BTKi. Lastly, treatment of RS-PDX mice with the combination of PI3Ki and OT-82 results in significant inhibition of tumor growth, with evidence of in vivo activation of apoptosis. Collectively, these data highlight a novel application for NAMPT inhibitors in combination with BTKi or PI3Ki in aggressive lymphomas.

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Anti-CD37 α-amanitin–conjugated antibodies as potential therapeutic weapons for Richter syndrome

Cited by 9 publications

References 26 publications

Exploring the next generation of antibody–drug conjugates

Exploring the next generation of antibody–drug conjugates

Immunological Aspects of Richter Syndrome: From Immune Dysfunction to Immunotherapy

A molecular circuit linking the BCR to the NAD biosynthetic enzyme NAMPT is an actionable target in Richter syndrome

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