Dose escalation immunoPET imaging of B7-H3 expression in glioblastoma tumor model using 89Zr-DFO-hu4G4

doi:10.21203/rs.3.rs-2871179/v1

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Dose escalation immunoPET imaging of B7-H3 expression in glioblastoma tumor model using 89Zr-DFO-hu4G4

https://doi.org/10.21203/rs.3.rs-2871179/v1

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Background

The non-invasive PET imaging using zrconium-89 labelled antibodys (Abs) can play important roles for personalized immunotherapeutic strategies. Hu4G4 was a humanized Abs of the transmembrance glycoprotein B7-H3, which has been approved as an attractive new target of cancer immunotherapy. This study aimed to investigate the PET imaging potential of ⁸⁹Zr labelled hu4G4 with a dose escalation design.

Methods

Hu4G4 was radiolabelled with ⁸⁹Zr after modification with p-SCN-deferoxamine. ⁸⁹Zr-Immuno-PET scans of the U87 xenograft mice were performed with 3 different Abs doses of ⁸⁹Zr-DFO-hu4G4 (0.33, 1.75 and 17.5 mg/kg bodyweight, respectively). The pharmacokinetic (PK) and biodistribution profiles were also determined by γ counting of blood samples and dissected organs and tissues.

Results

The prepared ⁸⁹Zr-DFO-hu4G4 had high radiochemical purity (RCP > 95%) and was stable in vitro (RCP > 90% within 168 h). The U87 tumors were clearly detected by the ⁸⁹Zr-DFO-hu4G4 PET imaging. The middle-dose Abs group had higher tumor-to-normal tissue (T/N) ratios and better tumor specific uptake of the tracer than the low and high dose Abs groups.

Conclusion

⁸⁹Zr-DFO-hu4G4 is a potential immunoPET imaging probe for clinical detection of B7-H3 expression in tumor. Also, the dose dependent results of ⁸⁹Zr-immuno-PET imaging provide important insight towards the Abs dosimetry for Abs-based imaging and therapy.

Dose escalation

89Zr

immuno-PET imaging

B7-H3

hu4G4

Development of monoclonal antibodies (Abs) have huge impact on medical indications, especially in cancer treatment [1]. Currently, more than 41 Abs were approved by FDA for cancer treatment, targeting a range of antigens over-expressed by tumor cells or in tumor microenvironment [2]. However, only a portion of patients could benefit from the immunotherapy with these Abs [3]. The personalized immunotherapy strategies with choice of highly tumor-specific target and precise evaluation of the antigen expression in individual cancer patient have been urged for approaching more effective immunotherapy outcomes [4, 5]. The transmembrance glycoprotein B7-H3, also known as CD276, was first cloned from a cDNA library of human dendritic cells in 2001[6]. Aberrant high B7-H3 expression has been found in tumor tissues, such as gliomas [7], gastric cancer [8], breast cancer [9], pancreatic cancer [10], prostate cancer [11], non-small cell lung cancer [12], but not in normal tissues, exhibiting significant association with negative prognosis and poorer clinical outcomes [13]. Therefore, B7-H3 has become an attractive target for both diagnosis and treatment of types of tumors.

Hu4G4 is a new humanized monoclonal IgG1 antibody of B7-H3 generated previously by our group, which was derived from the original murine antibody 4G4 of B7-H3 and had high binding ability with the external domain of B7-H3 (Data will be published elsewhere). The non-invasive PET imaging using zrconium-89 (⁸⁹Zr) labelled Abs, also known as ⁸⁹Zr-immuno-PET is a non-invasive tool that can be used to quantification of antibody uptake in tumours for predicting subsequent therapeutic effects and address optimal antibody dose levels for personalized treatment [14–16].

In this study we aim to investigate the preparation and PET imaging potential of ⁸⁹Zr labelled hu4G4. Dynamic ⁸⁹Zr-immuno-PET and gamma (γ) counting technique are used to measure the tumor uptake, biodistribution and pharmacokinetics of the ⁸⁹Zr-DFO-hu4G4 probe with a U87 glioblastoma xenograft mouse models and an antibody dose escalation design.

Reagents.

p-SCN-deferoxamine (p-SCN-DFO) was obtained from Macrocyclics, Inc. (USA). Dimethyl sulfoxide (DMSO) was obtained from Acros Organics. Na₂CO₃ and 2-[4‐(2‐hydroxyethyl)piperazin‐1‐yl] ethane sulfonic acid (HEPES) solution was obtained from Sigma‐Aldrich. PD-10 columns were obtained from Cytiva (USA). 89Zr-oxalate was purchased from Dongcheng AMS Pharmaceutical Co., Ltd. (Nanjing, China).

Cell culture and animal models.

The human glioblastoma cell lines U87 were kindly provided by Suzhou Bright Scistar Biotechnology Co., Ltd. and cultured in high glucose Dulbecco’s modified Eagle’s medium (Gibco, USA) supplemented with 10% fetal bovine serum (Gibco, USA) and 100 U/mL penicillin/streptomycin (Beyotime, China) at 37°C in a 5% CO₂ humidified cell incubator (Thermo, Germany).

U87 cells were harvested in their exponential growth phase and resuspended in 100 µL of phosphate-buffered saline (PBS) at a concentration of 2 × 10⁷ cells/mL. 100 µL U87 cell suspension (2 × 10⁶ cells/tumor) was subcutaneously injected into the left and right armpits (2 tumors/mouse) of 4- to 6-week-old female BALB/c nu/nu mice purchased from Shanghai Lingchang Biotechnology Co., Ltd., respectively. Tumors with a size of 100–150 mm³ were used for imaging and biodistribution studies. All animals were maintained and subjected to experimental protocols in accordance with Soochow University Institutional Animal Care guidelines.

Conjugation and radiolabeling with ⁸⁹ Zr.

The B7-H3-targeted antibody (hu4G4) was conjugated to the DFO chelator according to previously reported methods in the literature with some modifications [15]. Briefly, hu4G4 in 1 mL of Na₂CO₃/NaHCO₃ buffer was added to a 9-fold molar excess of the chelator p-SCN-DFO (dissolved in 20–30 µL DMSO) and stirred slowly at 37°C for 90 min. The conjugate DFO-hu4G4 was then purified with a PD-10 column.

Next, DFO-hu4G4 was radiolabeled with ⁸⁹Zr according to a previously established method. First, 25–40 µL of ⁸⁹Zr-oxalate stock solution (~ 0.38–1.9 MBq) was diluted 9-fold with 0.2 M HEPES, and the pH of the solution was adjusted to 7.0 with 0.1 M Na₂CO₃. Second, DFO-hu4G4 was added to the above solution and incubated at 37°C for 1.5 h to obtain ⁸⁹Zr-DFO-hu4G4, which was purified with PD-10 columns with 0.15 M acetate buffer, pH 7.2 as the eluent.

The radiochemical purity was determined by radio-HPLC on a Waters E2695 instrument with an online radioactivity detector (3600, Bioscan) using an SEC chromatogram (G3000SWXL, TOSOH). The radiochemical purity was also determined by radio-thin layer chromatography (radio-TLC, Bioscan Inc.) with 0.5 M citrate buffer (pH 5.0 as the mobile phase and glass fiber paper as the carrier).

The in vitro stability of ⁸⁹Zr-DFO-hu4G4 (approximately 5 MBq) was studied at different time points (0, 2, 16, 32, 60, 96, 120, 144, 168, 180 h) after radiolabeling in either acetate buffer or human plasma at 37°C by radio-TLC.

Dose escalation by ⁸⁹ Zr-immuno-PET imaging evaluation.

When the tumor volume reached 100–150 mm³, twelve mice were randomly assigned to 3 groups (n = 4). The design of the ⁸⁹Zr-DFO-hu4G4 dose-escalation study is shown in Table 1. The mice were anesthetized with a 1.5%-2.5% isoflurane/oxygen mixture post IV injection of ⁸⁹Zr-DFO-hu4G4 by intravenous bolus via the tail vein and then imaged with 10 min or 20 min long static micro-PET (Inveon, Siemens) scans performed at 2, 16, 32, 60, 90, 120, 144, 168 and 180 h. PET data were reconstructed by the ordered subset expectation maximization 3D (OSEM3D) algorithm. The percent injected dose per gram of tissue (%ID/g) in the regions of interest (ROIs) (such as the left/right tumors, heart, liver, spleen, arthrosis and muscle) was drawn and analyzed by ASIPro software, of which %ID/g was calculated by Eq. (1):

Table 1

Therapeutic study groups. Mice bearing U87 glioblastoma tumors received a single injection of the given agent (n = 4/dose)
Study group	Radio-activity (MBq)	Unlabeled hu4G4 per mouse (µg)	Dose(mg/kg)
Low-dose	0.38 ± 0.02	0	0.33
Medium-dose	2.04 ± 0.05	0	1.75
High-dose	1.90 ± 0.03	315	17.5

Ex vivo Biodistribution of ⁸⁹ Zr-DFO-hu4G4.

To analyze the ex vivo biodistribution of ⁸⁹Zr-DFO-hu4G4, blood samples (~ 10–20 µL for each sample) were collected from tail vein at 180 h post injection of the tracer and weighed immediately. Mice of each group (n = 4) were euthanized after the last PET imaging at 180 h, then the major tissues and organs (such as left/right tumor, brain, heart, liver, spleen, lung, kidney, bone marrow, arthrosis, muscle, stomach, intestines and ovaries) were collected and weighed immediately. 89Zr radioactivities of these samples were measured with a γ counter (2480 WIZARD2, Perkin Elmer).

Pharmacokinetics of ⁸⁹ Zr-DFO-hu4G4.

To observe the in vivo PK behavior of hu4G4, blood samples (~ 10–20 µL) were also collected from the tail vein of each mouse at 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 16 h, 32 h, 60 h, 90 h, 120 h, 144 h and 168 h time points, weighed immediately and measured with the γ counter. PK parameters (such as half-life (T_1/2) and AUC _{(0−180 h)}) were calculated with the %ID/g data of blood samples from tail vein over a period of 5 min to 180 h post injection of the tracer by DAS software (version: 1.1).

Patlak model to assess target engagement.

To assess target engagement, the Patlak model was used to analyze the tumor uptake by ⁸⁹Zr-immunoPET according to previous reports in the literature [15]. Through this model, nonspecific binding (A) and specific binding (B) can be calculated.

Tumor uptake can be classified into two parts: One is target-specific binding, which reflects irreversible internalization/residualization of ⁸⁹Zr-antibody, the other is nonspecific binding in the blood circulation and interstitial space. Through this model, the following Eq. (2) can represent the tumor uptake (%ID/g):

Equation 2 can then be transformed into

where A’ represents nonspecific binding, B’ represents specific binding and AUC(t) represents the area under the blood uptake (%ID/g)-time curve (0-t).

Statistical analysis.

GraphPad Prism (version 9) was used for statistical analyses. Quantitative results are presented as the mean ± standard deviation (SD) with all error bars denoting the SD. Statistical analyses were carried out with Student’s t test, and p values less than 0.05 were considered statistically significant.

Radiolabelling with ⁸⁹ Zr and Stability evaluation in vitro

The labeling scheme and structure of ⁸⁹Zr-DFO-hu4G4 are illustrated in Fig. 1a. HPLC chromatograms (Fig. 1b) showed the retention times of hu4G4, DFO-hu4G4, ⁸⁹Zr-DFO-hu4G4 and free-⁸⁹Zr are 12.9 min, 12.3 min, 12.0 min and 18.0 min, respectively. These results indicated that hu4G4 was successfully conjugated with DFO and radiolabelled with ⁸⁹Zr. The radiochemical purities (RCPs) of the ⁸⁹Zr-DFO-hu4G4 product were > 95% (Fig. 1c). Also, the ⁸⁹Zr-DFO-hu4G4 product had good stability (> 90%) in acetate buffer, pH 7.2 and serum during an incubation period of 180 h as measured by radio-TLC (Fig. 1d).

Dose escalation studies with PET imaging.

The schematic design of the dose-escalation ⁸⁹Zr-immuno-PET study with U87 glioblastoma xenograft mice is illustrated in Fig. 2a. The representative PET images of one mouse at various time points (Fig. 2b) revealed that ⁸⁹Zr-DFO-hu4G4 was mainly concentrated in the tumor, followed by the liver during 16–180 h post intravenous (IV) injection (Fig. 2c-e).

The tumor uptake (percent injected dose per gram of tissue, %ID/g) of ⁸⁹Zr-DFO-hu4G4 increased rapidly in 32 h post injection and reached a plateau at 60 h for each group. The ⁸⁹Zr radioactivity had accumulated in the tumors of the middle-dose group (16.51 ± 1.01%ID/g) were significantly higher than that of low-dose group (14.78 ± 1.13%ID/g, p < 0.01) and high-dose group (10.02 ± 2.18%ID/g, p < 0.001) at 180 h (Figure S1 a). The %ID/g values of heart, liver, and spleen decreased gradually over time from 2 h time point, and there was no statistical inter-group difference of %ID/g at same time points for each organ (Figure S1 b-d). The ⁸⁹Zr radioactivity in bone joints of each group increased gradually over time. Notably, the ⁸⁹Zr accumulation in bone joints at 180 h was reduced with increasing antibody dose of the ⁸⁹Zr-DFO-hu4G4 tracer by comparing the 3 groups. (Figure S1 e).

Ex vivo biodistribution of ⁸⁹ Zr-DFO-hu4G4.

To further determine the biodistribution of ⁸⁹Zr-DFO-hu4G4 with different antibody doses, the ex vivo measurement of the blood samples collected from tail vein, dissected organs and tissues from mice euthanized after the last PET scanning was performed by γ counting. The results are presented in Fig. 3and Table S1. The highest accumulation of radioactivity was found in the tumors. Moreover, tumor uptake of ⁸⁹Zr-DFO-hu4G4 of the middle-dose group (21.82 ± 1.61%ID/g) was significantly higher than either low-dose group (17.87 ± 2.78%ID/g) (p < 0.05) or high-dose group (12.69 ± 2.30%ID/g) (p < 0.001). The bone joint uptake of ⁸⁹Zr had a decreasing tendency with increasing antibody dose. These results were consistent with the PET imaging analyses. The bone marrow uptake of ⁸⁹Zr was lower than bone uptake (Table S1). Moreover, the bone marrow uptake had the similar decreasing tendency with increasing antibody dose to bone. The %ID/g values of bone marrow of low-dose group outclassed the middle-dose (p < 0.001) and high-dose (p < 0.001). The ⁸⁹Zr uptake were modest in blood, liver, spleen, lung and kidneys (2.2–4.8%ID/g) and smaller amounts of ⁸⁹Zr were in heart and ovaries (1.6–1.9%ID/g). Other organs had minimal accumulation of ⁸⁹Zr (< 1% ID/g) (Table S1).

Pharmacokinetics of ⁸⁹ Zr- DFO-hu4G4 in vivo.

As shown in Fig. 4a, the blood uptake of ⁸⁹Zr-DFO-hu4G4 approached 50.59 ± 5.52%ID/g, 44.24 ± 4.51%ID/g and 30.22 ± 6.17%ID/g, respectively for the low-dose, middle-dose and high-dose group in 10 min post injection, and then decreased gradually to 3.14 ± 2.33%ID/g, 2.72 ± 0.61%ID/g and 4.87 ± 2.71%ID/g at 180 h. The blood uptake data were fitted with two-compartment model. The acquired T_1/2 values of ⁸⁹Zr-ZFO-hu4G4 were 56.92 ± 23.33 h (T_1/2α phase, 2.63 h; T_1/2β phase, 71.08 h), 44.70 ± 9.70 h (T_1/2α phase, 1.9 h; T_1/2β phase, 69.78 h) and 56.50 ± 29.34 h (T_1/2α phase, 4.38 h; T_1/2β phase, 111.69 h), respectively, for the low-dose, middle-dose and high-dose groups, and had no significantly statistical difference among them (p > 0.05) (Fig. 4b, Table S2). The AUC _(0−180h) was 2154.04 ± 577.25%ID/g*h for the low-dose, which was slightly higher than the middle-dose (1652.39 ± 151.19%ID/g*h) and high-dose (1813.89 ± 528.54%ID/g*h) (Fig. 4c).

Patlak model to assess target engagement.

To verify tumor-specific targeting and determine whether the targeting property is dose dependence, the Patlak model was used to analyze the receptor occupancy of hu4G4. Schematic illustration of the Patlak model was shown in Fig. 5a. In addition, the resulted B values of tumor-specific uptake for each group were shown in Fig. 5b. The linear relationship of the Patlak plot was illustrated in Fig. 5c-e. Notably, The B value from Patlak model of the specific uptake in tumor with middle-dose (0.009 ± 0.001) were significantly higher than low-dose (0.005 ± 0.002) and high-dose (0.004 ± 0.002) (p < 0.001). Patlak plots also showed that the middle-dose had higher tumor/blood ratios than the other two groups (Fig. 5d versus Figures. 5c and 5e). These results suggests that the middle-dose of hu4G4 may be more appropriate for immuno-PET imaging than the other two doses.

Comparison of tumor to normal organ ratios.

To further characterize the effect of antibody dose of hu4G4 on tumor uptake of ⁸⁹Zr-DFO-hu4G4, we calculated the tumor to organ ratios by quantitative analysis of the PET images acquired at 180 h post IV injection of the tracer. The results showed that tumor to organ (heart/liver/spleen/muscle/blood) ratios of middle-dose group were statistically higher than that of low-dose and high-dose (Fig. 6a). The tumor to organ ratios derived from the %ID/g values of ex vivo samples displayed similar statistical results (Fig. 6b).

As we all know, the mass dose of antibody should be taken into account for antibody-based specific molecular probes and immunotherapeutic drugs, as it was an important parameter affecting their safety and efficacy [14]. Hu4G4 is a new humanized Ab of B7-H3, which is highly expressed in types of tumors and has become an attractive target for both diagnosis and treatment. In this study, dose-escalation PET imaging with ⁸⁹Zr-labeled hu4G4 was performed with three different doses (0.33, 1.75, 17.5 mg/kg) in U87-xenografted mice to characterize the tumor uptake, biodistribution and pharmacokinetics of the tracer.

⁸⁹Zr-DFO-hu4G4 tracer was prepared with high radiochemical purity and exhibited good stability in vitro. The U87 xenografted glioblastoma tumors were clearly observed by the immuno-PET images for all the 3 groups post IV injection of ⁸⁹Zr-DFO-hu4G4, and the tumor uptake was higher than the normal organs, indicating the tracer has strong tumor targeting ability and stability in vivo. Quantitative analysis of the dynamic PET images showed that the middle-dose group had highest ⁸⁹Zr accumulation in tumors than the low- and high-dose groups. A plausible explanation is that the tumor binding sites were not saturated by antibody in the low-dose and approaching saturation in middle-dose groups, whereas massive unlabeled antibody presenting in the high-dose group could competitively bind the tumor B7-H3 receptor and thus restrained the tumor uptake of the ⁸⁹Zr labeled tracer.

PET images and biodistribution determination of ex vivo samples showed that bone joints, bone marrow, liver and spleen had the highest levels of ⁸⁹Zr-DFO-hu4G4 engagement among the normal organs or tissues, thus these organs or tissue should be mostly concerned for potential toxicity [17, 18]. The ⁸⁹Zr accumulation in bone joints and bone marrow can be hypothesized due to the nontarget binding of ⁸⁹Zr-DFO-hu4G4 with bone marrow and slow dissociation of ⁸⁹Zr component from the tracer, respectively. Both the bone joint uptake and bone marrow uptake were decreased with increasing antibody dose, suggesting higher antibody dose may be a beneficial factor to reduce the radiation burden to hemopoietic system[19]. These findings affirmed that the antibody dose of ⁸⁹Zr labeled hu4G4 is a remarkable factor affecting the tumor uptake, biodistribution and potential toxicity.

Blood pharmacokinetic analysis showed that AUC _{(0−180 h)} in low-dose group was slightly higher than in the middle- and high-dose groups, and T_1/2 values had no difference among the 3 groups, demonstrating the antibody dose of ⁸⁹Zr-DFO-hu4G4 tracer had only trivial impact on the blood pharmacokinetics.

The tumor uptake of a PET imaging tracer can be attributed to two factors. One is target-specific binding, which reflects irreversible internalization/residualization of the tracer, the other is nonspecific binding in the blood circulation and interstitial space [14]. We analyzed the tumor receptor occupancy of ⁸⁹Zr-DFO-hu4G4 with the Patlak model. The middle-dose group had higher B value, which represents the tumor specific uptake property than the other two groups, implying the tumor target occupancy of ⁸⁹Zr-DFO-hu4G4 has not yet reached saturation in low-dose group, whereas in high-dose group the specific tumor target sites could be competitively occupied by the massive unlabeled antibody, thus restrained the specific tumor engagement of ⁸⁹Zr-DFO-hu4G4. The middle dose group also had relatively higher tumor to normal organ (liver, spleen, muscle and blood) ratios than low- and high-dose groups. Therefore, the appropriate chosen antibody dose of the tracer can produce more specific immuno-PET images.

A humanized anti-B7-H3 mAb, hu4G4 was successfully radiolabeled with ⁸⁹Zr with high radiochemical purity. The prepared ⁸⁹Zr-DFO-hu4G4 was approved by preclinical study to be a promising potential PET imaging probe for the non-invasive detection of B7-H3 positive tumor. The dose dependence feature of tumor uptake and biodistribution of ⁸⁹Zr-DFO-hu4G4 may provide important insight towards optimizing the antibody dosimetry for the development of immuno-PET imaging and immunotherapy.

Abs	Monoclonal antibodies
HEPES	2‐[4‐(2‐hydroxyethyl)piperazin‐1‐yl] ethane sulfonic acid
IV	intravenous
OSEM3D	ordered subset expectation maximization 3D
PET	Positron Emission Computed Tomography
p-SCN-DFO	p-SCN-deferoxamine
RCPs	radiochemical purities
ROIs	regions of interest
SD	standard deviation
T_1/2	half-life

Ethics approval and Consent to participate

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal procedures were conducted under a protocol approved by the Soochow University Institutional Animal Care. A statement confirming the study was carried out in compliance with the ARRIVE guidelines.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Competing interests

The authors declare that they have no conflict of interest.

Funding

This work was funded by National Natural Science Foundation of China (82104318), Key R&D Program of Jiangsu Province (BE2021644), the Project of State Key Laboratory of Radiation Medicine and Protection, Soochow University (No. GZK1202203), the Jiangsu Innovative and Enterpreneurial Talent Programme (JSSCBS20211568), the Science and Technology Plan of Suzhou (SKJYD2021161). No other potential conflict of interest relevant to this article was reported.

Authors’ contributions

MZ, SDZ and FQF performed all experiments, analyzed data and wrote the manuscript. YW and KJZ were assigned to radiolabel antibodies with ⁸⁹Zr. QFL and HWM carried out part of experiments. SHL, XGZ and LYM conceptualized the research and revised the manuscript. All authors have reviewed the manuscript.

Acknowledgments

The authors acknowledge the facilities and support of the personnel of the Jiangsu Institute of Nuclear Medicine.

Author’s details

¹ Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, NO.899 Pinghai Road, Suzhou 215006, China. ²Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, 215006, China.³State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China. ⁴Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, NO.178 Ganjiang Road, Suzhou 215000, China.

⁵SuZhou Bright Scistar Antibody Biotech co., Ltd, 303-305, Bldg 15, NO.8, Jinfeng Road, Suzhou New District, Jiangsu, Suzhou 215000, China.

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Dose escalation immunoPET imaging of B7-H3 expression in glioblastoma tumor model using 89Zr-DFO-hu4G4

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