Comparison of CD38-Targeted α- Versus β-Radionuclide Therapy of Disseminated Multiple Myeloma in an Animal Model

Minnix, Megan; Adhikarla, Vikram; Caserta, Enrico; Poku, Erasmus; Rockne, Russell C.; Shively, John E.; Pichiorri, Flavia

doi:10.2967/jnumed.120.251983

Cited by 29 publications

(30 citation statements)

References 32 publications

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“…Therefore, another merit of [ 68 Ga]Ga-NOTA-Nb1053 is that there is no need to administrate unlabeled Nb1053 to saturate the extremely high spleen uptake. As a companion diagnostic tool, [ 68 Ga]Ga-NOTA-Nb1053 immunoPET may optimize CD38-targeted radioimmunotherapy [33,34]. Considering that CD38 is an alternative tumor marker for other hematological malignancies [28], it is rational to expand the application scenarios of [ 68 Ga]Ga-NOTA-Nb1053.…”

Section: Discussionmentioning

confidence: 99%

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

Wang

Chen

Hou

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose Multiple myeloma (MM) remains incurable and its diagnosis relies heavily on bone marrow aspiration and biopsy. CD38 is a glycoprotein highly speci c for MM. Antibody therapeutics (e.g., daratumumab) targeting CD38 have shown encouraging e cacy in treating MM, either as a monotherapy agent or in combination with other regimens. However, e cient strati cation of patients who might bene t from daratumumab therapy and timely monitoring of the therapeutic responses are still clinical challenges. This work aims to devise a CD38-targeted imaging strategy and assess its value in diagnosing MMs.Methods By labeling a CD38-speci c single domain antibody (Nb1053) with 68 Ga (t 1/2 = 1.1 h), we developed a CD38-targeted immuno-positron emission tomography (immunoPET) imaging probe [ 68 Ga]Ga-NOTA-Nb1053. The probe was developed with good radiochemical yield (> 50%), excellent radiochemical purity (> 99%), and immunoreactivity (> 95%). The diagnostic accuracy of the probe was thoroughly investigated in preclinical MM models.Results ImmunoPET imaging with the probe speci cally depicted all the subcutaneous and orthotopic MM lesions, outperforming the traditional 18 F-uorodeoxyglucose PET and the nonspeci c [ 68 Ga]Ga-NOTA-NbGFP immunoPET. More importantly, daratumumab preloading signi cantly reduced [ 68 Ga]Ga-NOTA-Nb1053 uptake in the disseminated bone lesions, indicating the overlapping targeting epitopes of [ 68 Ga]Ga-NOTA-Nb1053 with that of daratumumab. Furthermore, premedication with sodium maleate or fructose signi cantly decreased kidney retention of [ 68 Ga]Ga-NOTA-Nb1053 and improved the diagnostic value of the probe in lymphoma models. ConclusionThis work successfully developed a novel CD38-targeted immunoPET imaging approach that enabled precise visualization of CD38 and diagnosis of MMs. Upon clinical translation, [ 68 Ga]Ga-NOTA-Nb1053 immunoPET may serve as a valuable CD38-targeted molecular imaging toolbox, facilitating early diagnosis of MM and precise assessment of the therapeutic responses.

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Section: Discussionmentioning

confidence: 99%

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

Wang

Chen

Hou

et al. 2021

Eur J Nucl Med Mol Imaging

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“…Mathematical models of tumor response to TRT and CAR-T cell therapies [10]have been described earlier [8,9,11]. The structure of the combined model is illustrated in Fig- ure 1B.…”

Section: Mathematical Modelmentioning

confidence: 99%

“…Thus, the quadratic term in Equation 4 is set to zero (i.e. = ) to model high linear-energy transfer (LET) alpha-particle based radiation. The initial dose rate is calculated as = where is a constant for conversion of injected activity to initial dose rate [9]. Mathematically, a treatment is "turned on" or off with the Heaviside function ( − ) which takes value zero for < before the start of treatment and unity for ≥ during and after treatment.…”

Section: Mathematical Modelmentioning

confidence: 99%

“…The parameters for 225 Ac-based TRT in the model ( , , { , } , ) were derived in our earlier work comparing beta-emitting ( 177 Lu-) and alpha-emitting ( 225 Ac-) radionuclides in multiple myeloma [9]. Model parameters related to CAR-T cells ( , , ) and the tumor growth rate ( ) were estimated experimentally with a mouse model of multiple myeloma as follows.…”

Section: Experimental Design and Model Parametrizationmentioning

confidence: 99%

“…We have previously published mathematical models for prediction of tumor response to CAR-T cell therapy in glioma [8], the Chimeric Antigen Receptor t-cell treatment Response in GliOma (CARRGO) and for targeted radionuclide therapy [9] in a preclinical multiple myeloma disease model. The purpose of this work is to combine two previously published mathematical models of CAR-T cell and TRT therapies and use the combined, and experimentally informed, model to explore the impact of dose, timing, and sequencing of these two therapies on tumor growth.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor-T Cell Combination Therapy

Adhikarla

Awuah

Brummer

et al. 2021

Preprint

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Targeted radionuclide therapy (TRT) has recently seen a surge in popularity, with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results – an example being chimeric antigen receptor (CAR) T-cells therapy in hematologic malignancies. Moreover, TRT and CAR T therapies possess unique features that require special consideration when determining how to dose, time, and sequence combination treatments, including the distribution of TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate additive or synergistic effects of combination therapies and warrant a mathematical treatment which includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here we combine two previously published mathematical models in a multiple myeloma setting to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell based therapies. We find that for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR T therapies.

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CD38‐Targeted Theranostics of Lymphoma with ⁸⁹Zr/¹⁷⁷Lu‐Labeled Daratumumab

Liu

Rosenkrans

et al. 2021

Advanced Science

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Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt′s lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38-targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr-89 and Lu-177 for theranostic applications. As the diagnostic component, the Zr-89-labeled mAb is highly specific in delineating CD38-positive lymphoma via positron emission tomography (PET) imaging, while the Lu-177-labeled mAb serves well as the therapeutic component to suppress tumor growth after a one-time administration. These results strongly suggest that CD38 is a lymphoma-specific marker and prove that 89 Zr/ 177 Lu-labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38-targeted theranostics may be of significant help in lymphoma patient stratification and management.

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Comparison of CD38-Targeted α- Versus β-Radionuclide Therapy of Disseminated Multiple Myeloma in an Animal Model

Cited by 29 publications

References 32 publications

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor-T Cell Combination Therapy

CD38‐Targeted Theranostics of Lymphoma with ⁸⁹Zr/¹⁷⁷Lu‐Labeled Daratumumab

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Comparison of CD38-Targeted α- Versus β-Radionuclide Therapy of Disseminated Multiple Myeloma in an Animal Model

Cited by 29 publications

References 32 publications

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor-T Cell Combination Therapy

CD38‐Targeted Theranostics of Lymphoma with 89Zr/177Lu‐Labeled Daratumumab

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CD38‐Targeted Theranostics of Lymphoma with ⁸⁹Zr/¹⁷⁷Lu‐Labeled Daratumumab