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Oncotarget: Tissue biodistribution and tumor targeting in preclinical multiple myeloma


Oncotarget published "Tissue biodistribution and tumor targeting of near-infrared labelled anti-CD38 antibody-drug conjugate in preclinical multiple myeloma" which reported that Daratumumab is an FDA-approved high-affinity monoclonal antibody targeting CD38 that has shown promising therapeutic efficacy in double refractory multiple myeloma patients. Despite the well-established clinical efficacy of DARA, not all heavily pretreated patients respond to single-agent DARA, and the majority of patients who initially respond eventually progress. In this study, the authors evaluated the anti-tumor efficacy of DARA conjugated to the maytansine derivative, mertansine, linked via a non-cleavable bifunctional linker.

Dr. Monica Shokeen from Washington University said, "Daratumumab (DARA) is a human IgG1 monoclonal antibody that targets Cluster of Differentiation 38 (CD38), inducing tumor cell death through multiple mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP)"

Despite the well-established clinical efficacy of DARA in relapsed and refractory multiple myeloma patients, not all of the heavily pretreated patients respond to single-agent DARA therapy, and the majority of patients who initially respond eventually progress. This may be due to upregulation of pathways that inhibit DARA-mediated ADCC and CDC. One possibility for enhancing the potency of DARA and increasing its therapeutic index is to introduce additional drugs to complement the multiple mechanisms of action of the native immunotherapy.

Antibody-drug conjugates combine the highly targeted tumor antigen recognition of antibodies with the cell killing properties of chemotherapy for effective internalization and processing of the drug. The ADC is designed to provide a wider therapeutic window than the antibody alone or the parent cytotoxic drug payload attached to it.

In this study, they evaluated the anti-tumor efficacy of DARA conjugated to the maytansine derivative, mertansine, linked via the non-cleavable bifunctional linker succinimidyl 4-cyclohexane-1-carboxylate. The SMCC linker contains a thioether bond, requiring complete lysosomal degradation of the ADC for intracellular release of the payload, and has demonstrated improved in vivo stability and reduced off-target toxicity compared to ADCs with cleavable linkers. The cleaved drug product, lysine-SMCC-DM1, contains a net positive charge, allowing for improved retention in the target cell following internalization of the ADC. The authors posit that DARA conjugated to DM1 via a non-cleavable linker will enhance the potency of the native DARA while maintaining high MM tumor specificity and in vivo stability.

The authors posit that DARA conjugated to DM1 via a non-cleavable linker will enhance the potency of the native DARA

Traditionally, such imaging studies are performed through imaging of radiolabeled compounds with Positron Emission Tomography or Single-Photon Emission Computed Tomography. While PET and SPECT are highly sensitive and can be used to measure tracer uptake into tissues, the use of decaying radioisotopes and ability to trace just one molecular species in a given imaging experiment does not allow for longitudinal monitoring of interactions between molecular targets. Labelling with fluorescent probes for optical imaging in the first near-infrared window allows for reduced autofluorescence in vivo than in the visible fluorescence range on a whole-body and cellular level in preclinical animal models. While there have been preclinical efforts in developing fluorescently-labelled ADCs for solid cancers, there have been no published studies evaluating fluorescently-labelled ADCs in preclinical models of MM or other hematologic malignancies.

Figure 5: Biodistribution and flow cytometric analysis of DARA-DM1-IR in MM.1S IV mice. (A) Normalized biodistribution (defined as TMR) of DARA-DM1-IR, DARA-IR and IgG-IR 9 days after administration of fluorescent conjugate. n = 3–4/group. Two-way ANOVA followed by Sidak's multiple comparisons test was performed on biodistribution data. (B) Flow cytometric analysis of IRDye800 MFIs from excised bone marrow of DARA-DM1-IR, DARA-IR and IgG-IR-injected mice. One-way ANOVA followed by Tukey's multiple comparisons test was performed on flow cytometry data. n = 3–4/group. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Error bars represent standard deviation.

The Shokeen Research Team concluded in their Oncotarget Research Output, "Our studies demonstrate that conjugation of DM1 to the native DARA significantly enhanced its therapeutic efficacy in vitro and in vivo. Fluorophore labelling did not affect the stability or activity of the biologic and showed that both DARA-IR and DARA-DM1-IR had similar binding and biodistribution profiles. These imaging techniques can be applied to other immunotherapies and antibody conjugates under investigation in animal models of diverse hematologic cancers to evaluate similar parameters demonstrated in this article. Future studies can help in mechanistically understanding these therapies to enhance response and overcome resistance in treatment of these cancers."

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DOI - https://doi.org/10.18632/oncotarget.28074

Full text - https://www.oncotarget.com/article/28074/text/

Correspondence to - Monica Shokeen - shokeenm@wustl.edu

Keywords - near-infrared (NIR) fluorescence, multiple myeloma (MM), cluster of differentiation 38 (CD38), antibody-drug conjugate (ADC), small animal optical imaging

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