3.7 Biodistribution in A375 and A549 tumor-bearing mice
As shown in Figure 4D, in the A375 xenograft model, the uptake values of89Zr-IP150 in tumors at 72, 120, and 168 h were
14.28±1.92, 17.13±3.74, and 20.29±0.74 ID%/g, respectively, which were
greater than those in other normal tissues. Co-injection of the
unlabeled precursor IP150 significantly reduced the tumor uptake of89Zr-IP150 at 168 h p.i. by ~53%
(p <0.01) but had no impact on normal tissues. In
addition, the uptake of 89Zr-IP150 in MUC18 (-) A549
tumors was comparable to that in normal tissues. These data suggest that
the uptake of 89Zr-IP150 was indeed mediated by MUC18.
Discussion
A growing body of research highlights the fundamental role of MUC18 in
various pathologic processes; for example, MUC18 promotes
atherosclerosis[27], induces insulin resistance
induced by obesity[28], and contributes to the
aggregation of infected red blood cells and
lymphocytes[29], and low expression of MUC18 also
leads to insufficient blood flow in the interstitial vascular
region[30]. The worldwide incidence of cutaneous
melanoma has been increasing annually at a more rapid rate than that of
any other type of cancer[31]. In contrast to the
increasing incidence of skin melanoma, the incidence of mucosal melanoma
has remained stable[32]. Early and accurate
diagnosis of melanoma can greatly improve patient survival. In addition
to the pathogenesis of each subtype of melanoma, the response to
BRAF/MEK mutation-targeted small molecule and immune checkpoint therapy
is different[17]; therefore, antibody-based drugs
targeting overexpressed tumor-associated antigens, such as ADC, are a
more universally effective treatment approach[33].
The dominant expression of MUC18 in melanomas (i.e., in approximately
70% of primary melanomas and 90% of lymph node metastases) makes this
marker a potential candidate for identifying primary and metastatic
melanomas; at present, the Class 1 biologic drug targeting MUC18 “ADC
AMT-253 for injection”, which has been approved for clinical research
in the treatment of advanced solid tumors. Moreover, we hypothesized
that IP150 would serve as an ideal targeting vector for the delivery of
RDC. Currently, there are reports of radionuclide probes targeting
MUC18, but the antibodies used are mouse-anti-human
mAbs[34], which may cause a human anti-mouse
antibody response and a low signal-to-noise ratio (SNR).
In this preclinical study, we propose an imaging approach that combines
the high sensitivity and SNR of PET imaging with the biomolecular
specificity of an anti-MUC18 humanized mAb for melanoma treatment.89Zr-IP150 is created by a high labeling rate,
superior radiochemical purity, and good stability. We used three
different MUC18 (+) melanoma cell lines as well as a MUC18 (-) cell line
to evaluate the specificity and targeting of the probe in vitro and
separately constructed subcutaneous CDX xenograft tumor models for in
vivo studies. In A375, SK-Mel-28, and HMVII tumor-bearing mice,89Zr-IP150 showed a favorable biodistribution in which
it selectively accumulated in tumors, was quickly cleared from the
blood, produced low background signals starting at 48 hours and
persisted at 168 hours post injection at the tumor site with high
sensitivity. Furthermore, the distribution of89Zr-IP150 was desirable, with less accumulation in
normal organs except for the liver, where exogenous antibodies are
cleared[35], which is desirable for PET imaging.
Figure 2 and Figure 3 show that 89Zr-IP150 also has
good specificity and targeting ability both in vivo and in vitro in a
mucosal melanoma model (HMVII). Although the incidence of mucosal
melanoma in the melanoma subtype is lower, the five-year survival rate
is only 25% due to the lack of early and effective diagnosis, so our
results may help these patients benefit from early and specific
diagnosis to choose a better treatment plan. Because human melanomas
consistently exhibit high glucose metabolism, 18F-FDG
PET/CT imaging is particularly well suited for detecting these
tumors[36]; however, we detected low radioactive
signals of 18F-FDG in both the A375 and HMVII CDX
models, possibly due to the inconsistency between human melanoma cell
metabolism in immunodeficient mice and human melanoma metabolism.
89Zr-IP150 also showed significant uptake in MUC18 (+)
PDX models of melanoma. We found that probe uptake in the PDX model
continued for up to 96 hours. In addition, increased spleen uptake was
also found in the PDX model.
These data may have implications for future clinical studies of ADC and
CAR-T-cell administration or177Lu/90Y-labeled IP150
antibody-targeted therapy in patients. In addition, as an important
tumor target, MUC18 is abnormally highly expressed in a variety of other
tumors, and high expression of MUC18 leads to poor prognosis in a
variety of tumors. In addition to these tumor types, studies have shown
that reduced MUC18 expression plays a role in inhibiting tumorigenesis
and carcinogenesis in colorectal cancer by inactivating the typical
Wnt/β-catenin cascade[37].
Conclusions
In conclusion, this study introduced the preclinical application of a
humanized radiolabeled MUC18-specific mAb probe, which was successfully
employed to image various mouse models of humanized melanoma.
Furthermore, the probe exhibited a promising targeting effect on tumors
in a clinically representative melanoma PDX model. Importantly, the
radiation dose in adults (0.065 mSv/MBq) was deemed relatively safe,
supporting its potential for future clinical translation.