CD38-specific immunoPET imaging for multiple myeloma diagnosis and therapeutic monitoring: preclinical and first-in-human studies, 2024, Huang et al.

SNT Gatchaman

SNT Gatchaman

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CD38-specific immunoPET imaging for multiple myeloma diagnosis and therapeutic monitoring: preclinical and first-in-human studies
Huang, Wenpeng; Wang, Tianyao; Qiu, Yongkang; Li, Chenzhen; Chen, Bo; Song, Lele; Yang, Qi; Sun, Xinyao; Jia, Bing; Kang, Lei

PURPOSE
CD38 is a glycoprotein highly specific to multiple myeloma (MM). Therapeutics using antibodies targeting CD38 have shown promising efficacy. However, the efficient stratification of patients who may benefit from daratumumab (Dara) therapy and timely monitoring of therapeutic responses remain significant clinical challenges. To address these issues, we developed a novel nanobody-based PET tracer, [68Ga]Ga-TOHP-CD3813, which exhibits rapid clearance from the blood and rapid accumulation in targeted tumor lesions, facilitating the detection of CD38 expression in murine models of MM and lymphoma. Furthermore, we conducted the world’s first-in-human trials using CD38-targeted nanobodies to validate and assess the clinical imaging effectiveness of [68Ga]Ga-TOHP-CD3813 in guiding cancer immunotherapy.

MATERIALS AND METHODS
We prepared a new PET imaging probe based on a CD38-targeted nanobody CD3813, [68Ga]Ga-TOHP-CD3813, via the site-specific radiolabeling for noninvasive PET imaging of CD38 expression. [68Ga]Ga-TOHP-CD3813 was assessed for its affinity and specificity to CD38 and its ability to image CD38 expression in MM and lymphoma xenograft models. Biodistribution and the relationship between tumor uptake and CD38 expression were evaluated. Subsequently, we conducted a translational PET imaging of 2 MM patients using [68Ga]Ga-TOHP-CD3813, while compared with [18F]FDG PET/CT head-to-head. Dosimetry was also calculated based on the animal data.

RESULTS
TOHP-CD3813 retained a high affinity for CD38 with a KD of 0.0826 nmol/L. [68Ga]Ga-TOHP-CD3813 was successfully synthesized at room temperature within 10 min, exhibiting optimal radiochemical properties. Preclinical assessments revealed rapid blood clearance, high CD38 affinity, and significant uptake in CD38-positive xenograft mouse models (6.50 ± 2.69%ID/g). [68Ga]Ga-TOHP-CD3813 showed pronounced accumulation in the kidneys and bladder, with moderate liver uptake, indicating its potential as a viable clinical PET radiotracer for diagnosing MM. Additionally, in first-in-human trials, [68Ga]Ga-TOHP-CD3813 PET/CT provides a substantial improvement over [18F]FDG PET/CT for the visualization of MM.

CONCLUSIONS
[68Ga]Ga-TOHP-CD3813, with its high affinity, specificity, and robust imaging capabilities, rapidly and specifically accumulates in tumors with high CD38 expression, offering a significant advantage over [18F]FDG PET/CT for visualizing MM and enabling same-day PET imaging. Initial human trial results are promising, suggesting its potential as a companion diagnostic tool for optimizing CD38-targeted treatments in tumors. Ongoing larger trials aim to further confirm these findings.

Web | PDF | European Journal of Nuclear Medicine and Molecular Imaging | Paywall
 
See also prior 2020 paper (also paywalled) —

CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human Imaging
Gary A Ulaner; Nicholas B Sobol; Joseph A O’Donoghue; Assen S Kirov; Christopher C Riedl; Ryan Min; Eric Smith; Lukas M Carter; Serge K Lyashchenko; Jason S Lewis; C Ola Landgren

ABSTRACT
An immuno-PET antibody composed of the native daratumumab labeled with the positron-emitting radionuclide zirconium 89 through the chelator deferoxamine, or 89Zr-DFO-daratumumab, demonstrated successful uptake in osseous deposits in patients with multiple myeloma.

BACKGROUND
Current measurements of multiple myeloma disease burden are suboptimal. Daratumumab is a monoclonal antibody that targets CD38, an antigen expressed on nearly all myeloma cells.

PURPOSE
To demonstrate preclinical and first-in-human application of an antibody composed of the native daratumumab labeled with the positron-emitting radionuclide zirconium 89 (89Zr) through the chelator deferoxamine (DFO), or 89Zr-DFO-daratumumab, for immunologic PET imaging of multiple myeloma.

MATERIALS AND METHODS
89Zr-DFO-daratumumab was synthesized by conjugating 89Zr to daratumumab with DFO. A murine xenograft model using CD38-positive OPM2 multiple myeloma cells was used to evaluate CD38-specificity of 89Zr-DFO-daratumumab. Following successful preclinical imaging, a prospective phase I study of 10 patients with multiple myeloma was performed. Study participants received 74 MBq (2 mCi) of intravenous 89Zr-DFO-daratumumab. Each participant underwent four PET/CT scans over the next 8 days, as well as blood chemistry and whole-body counts, to determine safety, tracer biodistribution, pharmacokinetics, and radiation dosimetry. Because 89Zr has a half-life of 78 hours, only a single administration of tracer was needed to obtain all four PET/CT scans.

RESULTS
89Zr-DFO-daratumumab was synthesized with radiochemical purity greater than 99%. In the murine model, substantial bone marrow uptake was seen in OPM2 mice but not in healthy mice, consistent with CD38-targeted imaging of OPM2 multiple myeloma cells. In humans, 89Zr-DFO-daratumumab was safe and demonstrated acceptable dosimetry. 89Zr-DFO-daratumumab uptake was visualized at PET in sites of osseous myeloma.

CONCLUSION
These data demonstrate successful CD38-targeted immunologic PET imaging of multiple myeloma in a murine model and in humans.

Web | PDF | Radiology | Paywall
 
Have I got this right: this imaging method is designed to show daratumumab uptake in myeloma, by using a tracer that accumulates in tissue with high expression of CD38 (i.e, myeloma tumours)?

If it is, would it be useable in people who don't have myeloma, and may not have high expression of CD38 either? ME/CFS might be linked to CD38, but presumably it doesn't necessarily follow that expression will be abnormally high.
 
Kitty said:
ME/CFS might be linked to CD38, but presumably it doesn't necessarily follow that expression will be abnormally high.
Click to expand...
It doesn't necessarily follow but there is a chance it might show something. If CD38 is involved it is likely to be because it is over-expressed by something.

The big problem is likely to be calibration, which seems to be tricky for these tracers if you are just looking for a change in intensity of binding. With myeloma/plasmacytoma you may be looking for local deposits and so using the tracer as a way to get a distribution pattern where calibration is less of an issue.
 
Kitty said:
Have I got this right: this imaging method is designed to show daratumumab uptake in myeloma, by using a tracer that accumulates in tissue with high expression of CD38 (i.e, myeloma tumours)?

If it is, would it be useable in people who don't have myeloma, and may not have high expression of CD38 either? ME/CFS might be linked to CD38, but presumably it doesn't necessarily follow that expression will be abnormally high.
Click to expand...
I hadn't thought about the fact it might not necessarily be involved because its high- good point.


Jonathan Edwards said:
The big problem is likely to be calibration, which seems to be tricky for these tracers if you are just looking for a change in intensity of binding. With myeloma/plasmacytoma you may be looking for local deposits and so using the tracer as a way to get a distribution pattern where calibration is less of an issue.
Click to expand...
Ah that sounds like it could be complicated.


I drafted an email to Michelle James yesterday but looking now she doesn't seem to have a contact email listed on her Stanford page.

I was also mulling over the idea of getting in touch with Fluge and Mella. I'm sure they are aware of this tracer as it is their field.

It sounds like if this hypothetical study could be made viable, a negative finding wouldnt rule out CD38 involvement but a positive one could be really useful.


@SNT Gatchaman do you think this could be a worthwhile tracer to use in ME/CFS? And I remember that this kind of scan doesn't show lymph nodes, but am I right in thinking it does show bone marrow?
 
V.R.T. said:
@SNT Gatchaman do you think this could be a worthwhile tracer to use in ME/CFS? And I remember that this kind of scan doesn't show lymph nodes, but am I right in thinking it does show bone marrow?
Click to expand...

It's potentially worth exploring. Eg there's a possibility we might find it to be a way of predicting response to dara. In theory it should tag any cells expressing CD38 so if those cells are present in sufficient numbers that would light up any tissue. For LLPCs that would be marrow, gut lymphoid tissue and spleen.

It would be good to hear expert thoughts, so thank you for emailing Michelle James.
 
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