Overcoming resistance to rituximab in relapsed non-Hodgkin lymphomas by antibody-polymer drug conjugates actively targeted by anti-CD38 daratumumab

Lidický, Ondřej; Klener, P; Machová, Daniela; Vočková, Petra; Pokorná, Eva; Helman, Karel; Mavis, Cory; Janoušková, Olga; Etrych, Tomáš

doi:10.1016/j.jconrel.2020.08.042

Cited by 12 publications

(7 citation statements)

References 48 publications

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“…Various structures including diblocks, multiblocks, grafts, or star-like shapes were developed (Figure 4), and their enhanced treatment efficacy compared to the first-generation HPMA copolymers was confirmed in vivo on animal models of both solid tumors and hematological malignancies [98]. Besides the passive accumulation of the attached drugs achieved predominantly by the EPR effect, HPMA copolymers can be effectively modified as active targeting systems, most frequently by the conjugation of various monoclonal antibodies or their fragments [99] (Figure 4). In addition, HPMA-based nanomedicines can serve as effective theranostics [100].…”

Section: Hpma-based Polymersmentioning

confidence: 99%

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas

Etrych

Braunová

Zogala

et al. 2022

Cancers

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Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody–drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of “old” cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.

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Section: Hpma-based Polymersmentioning

confidence: 99%

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas

Etrych

Braunová

Zogala

et al. 2022

Cancers

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“…Nevertheless, the antibody-targeted pHPMA nanomedicines reached significant benefits in the treatment efficacy in the case of various hematological malignancies studies in vivo. Various lymphomas [121,122] and leukemias [123,124] have been efficiently eradicated by the antibody-targeted pHPMA conjugates, showing the potential of the active targeting in the case of hematological malignancies, which are known for low genetic mutations in contrast to other solid tumors [93].…”

Section: Active Targeting Versus Passive Accumulation Of Phpma Nanomementioning

confidence: 99%

HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery

Chytil

Kostka

Etrych

2021

JPM

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Recently, numerous polymer materials have been employed as drug carrier systems in medicinal research, and their detailed properties have been thoroughly evaluated. Water-soluble polymer carriers play a significant role between these studied polymer systems as they are advantageously applied as carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, antimicrobial molecules, or multidrug resistance inhibitors. Covalent attachment of carried molecules using a biodegradable spacer is strongly preferred, as such design ensures the controlled release of the drug in the place of a desired pharmacological effect in a reasonable time-dependent manner. Importantly, the synthetic polymer biomaterials based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are recognized drug carriers with unique properties that nominate them among the most serious nanomedicines candidates for human clinical trials. This review focuses on advances in the development of HPMA copolymer-based nanomedicines within the passive and active targeting into the place of desired pharmacological effect, tumors, inflammation or bacterial infection sites. Specifically, this review highlights the safety issues of HPMA polymer-based drug carriers concerning the structure of nanomedicines. The main impact consists of the improvement of targeting ability, especially concerning the enhanced and permeability retention (EPR) effect.

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“…This will be evaluated in our future research. Notably, in relapsed non-Hodgkin lymphoma [47] and diffuse large B-cell lymphoma [48] successful treatment of patient derived xenografts was achieved by replacing anti-CD20 RTX with anti-CD38 DARA or DARA-drug conjugates. Our data combined with these results suggests that treatment of lymphoma patients with therapies involving both antibodies might be beneficial.…”

Section: Simultaneous Crosslinking Of Cd38 and Cd20 Receptors Enhances Apoptosismentioning

confidence: 99%

Crosslinking of CD38 Receptors Triggers Apoptosis of Malignant B Cells

Gambles

Wang

et al. 2021

Molecules

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Recently, we designed an inventive paradigm in nanomedicine—drug-free macromolecular therapeutics (DFMT). The ability of DFMT to induce apoptosis is based on biorecognition at cell surface, and crosslinking of receptors without the participation of low molecular weight drugs. The system is composed of two nanoconjugates: a bispecific engager, antibody or Fab’ fragment—morpholino oligonucleotide (MORF1) conjugate; the second nanoconjugate is a multivalent effector, human serum albumin (HSA) decorated with multiple copies of complementary MORF2. Here, we intend to demonstrate that DFMT is a platform that will be effective on other receptors than previously validated CD20. We appraised the impact of daratumumab (DARA)- and isatuximab (ISA)-based DFMT to crosslink CD38 receptors on CD38+ lymphoma (Raji, Daudi) and multiple myeloma cells (RPMI 8226, ANBL-6). The biological properties of DFMTs were determined by flow cytometry, confocal fluorescence microscopy, reactive oxygen species determination, lysosomal enlargement, homotypic cell adhesion, and the hybridization of nanoconjugates. The data revealed that the level of apoptosis induction correlated with CD38 expression, the nanoconjugates meet at the cell surface, mitochondrial signaling pathway is strongly involved, insertion of a flexible spacer in the structure of the macromolecular effector enhances apoptosis, and simultaneous crosslinking of CD38 and CD20 receptors increases apoptosis.

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Overcoming resistance to rituximab in relapsed non-Hodgkin lymphomas by antibody-polymer drug conjugates actively targeted by anti-CD38 daratumumab

Cited by 12 publications

References 48 publications

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas

Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas

HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery

Crosslinking of CD38 Receptors Triggers Apoptosis of Malignant B Cells

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