Biodistribution and Dosimetry of In-111/Y-90-HuCC49ΔCh2 (IDEC-159) in Patients with Metastatic Colorectal Adenocarcinoma

Abstract

Background:

CC49, an antibody (mAb) reactive to tumor-associated glycoprotein (TAG-72), has been extensively studied for radioimmunotherapy for colon cancer. Myelotoxicity has been dose-limiting because of prolonged circulation time in the plasma, and human anti-mouse antibody responses were observed in the majority of patients. A CH2 domain deleted and humanized CC49 (HuCC49ΔCh2) was developed to ameliorate these problems. This study reports biodistribution and dosimetry of ¹¹¹In/⁹⁰Y-HuCC49ΔCh2 (IDEC-159).

Materials and Methods:

Five (5) patients with colon cancer were enrolled. Each patient received intravenous administration of 185 MBq ¹¹¹In-HuCC49ΔCh2, followed by sequential gamma camera imaging, and blood counting. Uptakes and clearance half-lives for organs and tumors were quantified from images. Absorbed doses for ⁹⁰Y-HuCC49ΔCh2 were derived from ¹¹¹In-HuCC49ΔCh2 kinetic data.

Results:

Compared to reported ¹¹¹In/⁹⁰Y-CC49 data in the literature, median blood circulation T_1/2β was less at 38 (31–43) hours for ⁹⁰Y-HuCC49ΔCh2, than 50 hours for ⁹⁰Y-CC49. Median tumor-to-marrow absorbed dose ratio was 18 for ⁹⁰Y-HuCC49ΔCh2, and 9.53 for ⁹⁰Y-CC49. Median tumor-to-liver absorbed dose ratio was 3.14 for ⁹⁰Y-HuCC49ΔCh2, and 1.0 for ⁹⁰Y-CC49. Median tumor-to-spleen absorbed dose was 3.19 for ⁹⁰Y-HuCC49ΔCh2, and 1.07 for ⁹⁰Y-CC49.

Conclusions:

A humanized and CH2 domain-deleted CC49 antibody radiolabeled with ¹¹¹In/⁹⁰Y showed improved tumor-to-normal dose ratios over those reported from studies with intact CC49.

Introduction

Colorectal cancer is the third most common cancer in the United States. When colorectal cancer is detected at an early and localized stage, it can often be cured. However, if the cancer has spread to adjacent lymph nodes, organs, or to distant parts of the body, the survival rates decrease substantially. Several chemotherapeutic agents have been used as first- and second-line treatment of Stage IV colorectal cancer; however, they do not provide satisfactory tumor control and often result in significant toxicities that severely lower the quality of life in patients with limited life expectancy. External beam radiotherapy is sometimes used for treatment of unresectable or metastatic tumors, but its success has been limited due to difficulty in irradiating multiple metastatic sites.

Radioimmunotherapy has the potential to systemically deliver localized radiation through an antibody directed to a tumor-associated antigen. Encouraging results have been obtained in radioimmunotherapy for lymphoma,^1

–4 and ⁹⁰Y-ibritumomab and ¹³¹I-tositumomab are approved for routine treatment. Murine CC49 labeled with ¹³¹I, ¹⁷⁷Lu, or ⁹⁰Y has been widely studied as a therapy for colon^5
–7 and refractory metastatic gastrointestinal cancer.^8,9 However, the efficacy of CC49 antibodies has not been well demonstrated due to human anti-mouse antibody responses, which prevented repeat doses, and prolonged circulation time that limited dose escalation due to bone marrow toxicities.

A humanized, CH2 domain-deleted version of CC49 (HuCC49ΔCh2) was developed to address the above two shortcomings by Dr. Schlom and his colleagues at the National Cancer Institute.^10,11 The use of humanized molecules can reduce immunogenicity and the deletion of CH2 constant region can reduce the circulation time in plasma.¹² These two combined characteristics may have the potential to improve tumor-to-normal tissue absorbed dose ratio. To assess this potential, patients with metastatic colorectal adenocarcinoma were enrolled in a clinical trial using ¹¹¹In/⁹⁰Y-HuCC49ΔCh2 (IDEC-159). The current analysis describes the pharmacokinetics, biodistribution, and dosimetry of ⁹⁰Y-HuCC49ΔCh2 in patients based on sequential imaging of ¹¹¹In-HuCC49ΔCh2.

Materials and Methods

Patients

Four (4) male and 1 female patients (n = 5) with pathologically confirmed metastatic colorectal adenocarcinoma were enrolled in this study. These patients failed to respond or relapsed following 5-FU, irinotecan, oxaliplatin, bevacizumab, or cetuximab. They had recovered from any significant toxicity associated with prior surgery, chemotherapy, biological therapy, or investigational drug. All patients had radiographically measurable disease. After signing a written Informed Consent form approved by institutional review board of University of Alabama Birmingham, each patient received intravenous administration of 185 MBq (5 mCi) ¹¹¹In-IDEC-159 followed by sequential whole-body gamma camera imaging.

¹¹¹In/⁹⁰Y- HuCC49ΔCh2 (IDEC-159)

HuCC49ΔCh2 is derived from a genetically engineered, humanized, CH2 domain-deleted, IgG1 kappa MAb, with a molecular weight of ∼120 kDa, that specifically binds to tumor-associated glycoprotein (TAG-72). There is an intact hinge region with a 10 amino acid (gly/ser) linker peptide bridging CH1 and CH3 constant domains. The light chain transfectants were selected for neomycin resistance with G418 and were cloned twice. The HuCC49ΔCh2 heavy chain was then introduced into the highest titer light chain producing line. These double transfectants were selected for mycophenolic acid resistance and cloned twice.¹³ IDEC-159 is a HuCC49ΔCh2 conjugated to cyclohexyl-diethylenetriaminepentaacetate chelator via a stable thiourea linkage using conjugation conditions to achieve 0.9–1.8 chelates per antibody. The conjugated product is labeled with either ¹¹¹In (¹¹¹In-HuCC49ΔCh2) for imaging and dosimetry or ⁹⁰Y (⁹⁰Y-HuCC49ΔCh2) for the therapeutic treatment. All quality assurance criteria were met, with radiochemical purity of ¹¹¹In- HuCC49ΔCh2 or ⁹⁰Y- HuCC49ΔCh2 >95%.

Quantification of ⁹⁰Y/¹¹¹In in blood

Whole blood samples were collected within 10 minutes, and at 2, 4, 6, 8, 24, 32, 48, 72, 144, and 168 hours after the administration of ¹¹¹In-HuCC49ΔCh2. ¹¹¹In activity was measured using a gamma well-counter and counts from the sample were converted to activity by co-counting samples with a reference source. The reference source containing 19 kBq (0.5 μCi) ¹¹¹In in 1 mL was pipetted from a calibrated stock solution with known concentration.¹⁴ Activities of ¹¹¹In-HuCC49ΔCh2 were corrected for decay of the radioisotope from the time of drug administration to the time of measurement. ⁹⁰Y-HuCC49ΔCh2 activity in the whole blood was derived from ¹¹¹In activity adjusted by the small difference in physical decay half-life. ⁹⁰Y-HuCC49ΔCh2 concentration was expressed as percentage of injected dose/mL (%ID/mL) and analyzed using a bi-exponential clearance (α and β) model. The cumulated activity or residence time was determined using the bi-exponential clearance parameters.

Quantitative imaging

More detailed description on imaging and data methods for ¹¹¹In has been previously reported.¹⁴ Planar conjugate whole body images were acquired with a dual-detector gamma camera interfaced to a nuclear medicine computer system. Medium energy collimators were used to image ¹¹¹In with energy windows centered at 171 and 245 keV (15% width). Transmission scan images were obtained using a ⁵⁷Co sheet source. The same medium energy collimators were used to image ⁵⁷Co with an energy window centered at 122 keV (15% width). Planar conjugate views of the whole body were acquired immediately (within 1 hour) after administration of ¹¹¹In-HuCC49ΔCh2, and at 4–6, 24, 48–72, and 120–144 hours for a total of five scans. Each patient's position on the imaging table and vertical positions of the camera detectors were recorded in the first imaging session and were used throughout the sequential imaging studies for reproducible detector-to-patient positioning. A 10 mL ¹¹¹In reference source containing 1.9 MBq (50 μCi) was placed on the imaging table at least 10 cm away from the patient's feet. This calibrated source was used to correct for potential system drift and to convert image region-of-interest (ROI) counts to units of radioactivity adjusted for experimentally measured volume effect.^14,15

Major organs that were visible above body background after clearance of the blood pool were contoured, except for bladder. Tumors were only quantified if they met the following criterion for adequate accuracy: (1) ≥1 cc in volume, (2) tumor-to-background pixel counts ratio ≥1.5, and (3) clear tumor ROI boundary.¹⁶ Counts in selected ROIs were corrected for background. The thickness of the background region chosen was equivalent, after accounting for photon attenuation, to the overlapped background tissues in the organs from the anterior and posterior views.

Radioactivities in the liver, lungs, and heart were assessed using the geometric-mean quantification.^17
–19 The attenuation correction factor was determined for liver, lungs, and heart using ROI counts in the ⁵⁷Co transmission images with and without the patient, and then correcting for energy differences between ⁵⁷Co and ¹¹¹In based on phantom measurements.^14,16 For a source organ that can be clearly observed only in a single view, previous study suggested that source quantification using a single view (Effective Point Source) is more suitable than using conjugated views.^18,20 Therefore, kidney, spleen, and tumor activity was quantified using an Effective Point Source method.^14,19 The effective linear attenuation coefficient was determined using phantoms of 150 and 50, and 10 mL. The depth of kidneys, spleen, and tumors from the body surface was measured from CT images.

Uptake of ⁹⁰Y/¹¹¹In in organs and tumors was expressed as %ID at various imaging time points. Cumulated activity (and residence time) and biological clearance half-life (T_b1/2) were determined by fitting the uptake data with a mono-exponential curve. If fit of a mono-exponential curve was not possible as uptake data continuously increased during the period of sequential imaging, cumulated activity was determined using the trapezoid method, and a conservative estimation of the terminal clearance rate was achieved by setting it equal to the physical half-life. The cumulated activity or residence time of ⁹⁰Y was determined from the biodistribution of ¹¹¹In and adjusted for the small difference in physical half-life between ¹¹¹In and ⁹⁰Y.

Organ and tumor volume measurements

CT images prior (within 28 days) to first injection of 185 MBq (5 mCi) of ¹¹¹In-HuCC49ΔCh2 were used to determine a patient-specific organ mass to increase the accuracy of the dose estimate. Volume measurements were performed on CT DICOM images using Eclipse 3D radiotherapy treatment planning system (Varian Medical System, Palo Alto, CA). The tumor, liver, spleen, kidney, and heart volumes were manually defined by individual slice contour drawings on 5-mm-thick slices. Lung volumes were determined using a contrast-difference edge-detection method with manual correction for air in the main bronchi. A nominal tissue density of 1 g/cm³ was used for soft tissues except for the lungs, where the lung density assumed to be 0.26 g/cm³.²¹ The heart region was defined as extending below the level in which the pulmonary trunk branches into the left and right pulmonary arteries. The cumulated activity in the heart wall was estimated by subtracting cumulated blood activity. The mass of the individual heart wall and content was estimated assuming a ratio of 316/770 between reference heart wall and heart (wall + content).²²

Radiation dosimetry with patient-specific organ mass

Residence times for liver, spleen, kidneys, lungs, heart, tumor, and total body were determined from quantitative imaging, and residence time for marrow was determined from counting as described above. These residence times were input into the OLINDA-EXM program for absorbed dose calculation.²¹ The voiding bladder module in the OLINDA-EXM was used assuming an averaging voiding interval of 4 hours (3 hours during the day and 6 hours during 8 hours of sleep). Masses of liver, spleen, kidneys, lungs, heart wall, and body of individual patients were used to modify phantom masses in the OLINDA-EXM program.

Tumor mass and residence time were input into Spherical Model module of the OLINDA-EXM program for tumor dose calculation.^{21 90}Y concentration in red marrow was determined using RMBLR (red marrow-to-blood concentration ratio) described by Sgouros.²³ Although residence time of red marrow for each patient was calculated assuming reference mass of 1120 g, the dosimetry result of red marrow from blood was still patient-specific for ⁹⁰Y because patient-specific marrow dose from beta emissions in the blood does not require an explicit estimate of marrow mass.²⁴

Results

Quantification of ¹¹¹In/⁹⁰Y in blood

The bi-phasic clearance curves of ¹¹¹In-HuCC49ΔCh2 in the blood are illustrated in Figure 1. Blood activities versus time fit well with a bi-exponential model. The coefficient of determination (R ²) for bi-exponential curve fitting was ≥0.99 for all subjects. The median initial ¹¹¹In-HuCC49ΔCh2 (or ⁹⁰Y-HuCC49ΔCh2) concentration measured within 10 minutes postinjection was 0.0191%ID/mL (range 0.0150–0.0351) (Table 1). The median effective half-life was 3.4 hours (range 1.8–5.8) for the α clearance phase for ¹¹¹In-HuCC49ΔCh2 or ⁹⁰Y-HuCC49ΔCh2. The median effective half-life was 38.0 hours (range 30.5–43.0) for the β clearance phase for ¹¹¹In-HuCC49ΔCh2, and was 39.3 hours (range 31.4–44.7) for ⁹⁰Y-HuCC49ΔCh2. The median intercept for β clearance phase was 72% (range 64%–79%) of the initial ¹¹¹In-HuCC49ΔCh2 concentration in the blood.

FIG. 1.

⁹⁰Y-HuCC49ΔCh2 concentration over time in the blood. Blood activities as percentage of injected dose/mL (%ID/mL) versus time fit well with a bi-exponential model (R ² >0.99). All subjects had similar α and β clearance phases (Table 1).

Table 1.

Initial Concentration (Collected Within 10 Minutes Postinjection) and Bi-Phasic Clearance Half-Lives of ¹¹¹ In-HuCC49ΔCh2 in Blood

	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5
Initial concentration (%ID/mL)	0.0177	0.0150	0.0207	0.0191	0.0351
Alpha (α) phase half-life (h)	3.4	3.4	5.8	2.8	1.8
Beta (β) phase half-life (h)	41.8	38.0	43.0	35.9	30.5
Beta (β) phaseIntercept (%ID/mL)	0.0127	0.0114	0.0136	0.0150	0.0223

%ID/mL, percentage of injected dose/mL.

Organ and tumor masses

The median and range for body weights was 74,100 g (range 57,200–111,000). The median and range for organ mass was 1737 g (range 1503–2316) for liver, 263 g (127–417) for spleen, 387 g (269–532) for kidneys, 1039 g (925–1350) for lungs, 759 g (660–792) for heart, and 311 g (271–325) for heart wall. Median tumor mass was 31 g and ranged from 21 to 75 g. These median values deviated only modestly from the organ masses of the reference adult used in OLINDA/EXM (Table 2).

Table 2.

Body Weights and Organ/Tumor Masses of Individual Patients Measured from CT Images

Mass (g)	Subject 1	Subject 2	Subject 3	Subject 4	Subject 5	Reference mass in OLINDA
Body	71,200	74,100	103,600	111,000	57,200	73,700
Liver	1212	1737	2177	2316	1503	1910
Spleen	228	308	127	263	417	183
Kidneys	271	387	405	532	269	299
Lungs	1322	1350	1039	925	1001	1000
Heart	627	792	791	759	660	770
Heart wall	257	325	325	311	271	316
Tumor	31	21	28	75	44	NA

CT, computed tomography; NA, not applicable.

Derived biodistribution of ⁹⁰Y in organs and tumor

The peak uptake for heart, lungs, and spleen occurred at the initial imaging time point collected within 1 hour postinjection. The peak uptake for liver and tumor occurred at 4 hours postinjection. The peak uptake for kidneys occurred at 24 hours postinjection. Except in patient 4, tumors had higher peak uptake per gram of tissue mass (%ID/g) compared to normal organs (Table 3). The median (range) peak uptake was 0.0234%ID/g (0.0128–0.0656) for tumor, 0.0074%ID/g (0.0061–0.0085) for liver, 0.0119%ID/g (0.0088–0.0140) for spleen, 0.0147%ID/g (0.0061–0.0198) for kidneys, 0.0158%ID/g (0.0132–0.0212) for heart, and 0.0046%ID/g (0.0029–0.0063) for lungs.

Table 3.

Organ and Tumor Peak Uptake (%ID/g) and Effective Clearance Half-Life, T_½ef _f (Hours), of ⁹⁰ Y-HuCC49ΔCh2 (Derived from ¹¹¹ In-HuCC49ΔCh2)

	Subject 1		Subject 2		Subject 3		Subject 4		Subject 5
	Peak uptake (%ID/g)	T_1/2eff (hours)	Peak uptake (%ID/g)	T_1/2eff (hours)	Peak uptake (%ID/g)	T_1/2eff (hours)	Peak uptake (%ID/g)	T_1/2eff (hours)	Peak uptake (%ID/g)	T_1/2eff (hours)
Body	0.0014	54.1	0.0013	55.8	0.0010	51.8	0.0009	47.6	0.0017	49.5
Liver	0.0085	74.3	0.0061	68.0	0.0064	66.3	0.0074	74.1	0.0080	58.2
Spleen	0.0088	84.2	0.0140	57.7	0.0119	80.5	0.0131	48.8	0.0108	67.3
Kidneys	0.0198	48.1	0.0061	59.9	0.0186	44.2	0.0147	62.3	0.0145	55.6
Heart	0.0154	34.5	0.0132	32.1	0.0158	33.1	0.0212	15.0	0.0206	30.0
Lungs	0.0038	37.6	0.0029	41.6	0.0046	35.0	0.0063	39.7	0.0056	25.2
Tumor	0.0234	96.4	0.0206	70.7	0.0413	NA^a	0.0128	67.6	0.0656	56.2

Clearance half-life was not available because tumor uptake continuously increased within 168 hours sequential imaging.

In general, the effective clearance half-life of ⁹⁰Y-HuCC49ΔCh2 in the heart was shorter than the half-life in other organs, and tumors had a longer half-life than normal organs (Table 3). The median (range) effective clearance half-life was 51.8 hours (47.6–55.8) for the whole body, 68.0 hours (58.2–74.3) for liver, 67.3 hours (48.8–84.2) for spleen, 55.6 hours (44.2–62.3) for kidneys, 32.1 hours (15.0–34.5) for heart, 37.6 hours (25.2–41.6) for lung, and 70.7 hours (56.2—not available) for tumors. Clearance half-life was not available for one tumor as tumor uptake continuously increased within 168 hours sequential imaging.

Derived ⁹⁰Y-HuCC49ΔCh2 dosimetry

Radiation dosimetry for ⁹⁰Y-HuCC49ΔCh2 was determined based on measured tissue mass (Table 4). The median total body dose was 0.562 Gy/GBq (2.08 rad/mCi) and ranged from 0.316 to 0.646 Gy/GBq (1.17–2.39 rad/mCi). The median liver dose was 4.19 Gy/GBq (15.5 rad/mCi) and ranged from 3.19 to 4.97 Gy/GBq (11.8–18.4 rad/mCi). The median spleen dose was 5.68 Gy/GBq (21.0 rad/mCi) and ranged from 4.81 to 8.16 Gy/GBq (17.8–30.2 rad/mCi). The median kidney dose was 5.92 Gy/GBq (21.9 rad/mCi) and ranged from 4.32 to 9.30 Gy/GBq (16.0–34.4 rad/mCi). The median heart wall dose was 3.92 Gy/GBq (14.5 rad/mCi) and ranged from 3.73 to 4.65 Gy/GBq (13.8–17.2 rad/mCi). The median lung dose was 0.916 Gy/GBq (3.39 rad/mCi) and ranged from 0.865 to 1.50 Gy/GBq (3.20–5.54 rad/mCi). The median marrow dose from ⁹⁰Y in the blood was 0.865 Gy/GBq (3.20 rad/mCi) and ranged from 0.641 to 0.973 Gy/GBq (2.37–3.60 rad/mCi). The median tumor dose was 15.6 Gy/GBq (57.8 rad/mCi) and ranged from 6.22 to 34.8 Gy/GBq (23.0–129 rad/mCi).

Table 4.

Derived ⁹⁰ Y-HuCC49ΔCh2 Dosimetry Based on Measured Organ and Tumor Masses

	Subject 1		Subject 2		Subject 3		Subject 4		Subject 5
	Gy/GBq	cGy/mCi	Gy/GBq	cGy/mCi	Gy/GBq	cGy/mCi	Gy/GBq	cGy/mCi	Gy/GBq	cGy/mCi
Body	0.57	2.12	0.56	2.08	0.37	1.36	0.32	1.17	0.65	2.39
Liver	4.97	18.4	3.19	11.8	4.19	15.5	4.73	17.5	3.84	14.2
Spleen	4.89	18.1	5.68	21.0	8.16	30.2	4.81	17.8	5.70	21.1
Kidneys	9.30	34.4	4.89	18.1	4.32	16.0	6.30	23.3	5.92	21.9
Heart wall	4.65	17.0	4.24	15.7	3.78	14.0	3.92	14.5	3.73	13.8
Lungs	0.865	3.20	0.916	3.39	1.15	4.26	1.50	5.54	0.914	3.38
Marrow from blood	0.865	3.20	0.754	2.79	0.914	3.38	0.641	2.37	0.973	3.60
Tumor	15.6	57.8	8.00	29.6	34.8	129	6.22	23.0	29.2	108

Discussion

CC49 is a second-generation murine antibody with anti-TAG-72 reactivity to adenocarcinomas. The TAG-72 antigen, characterized as a high-molecular-weight glycoprotein with mucin properties, was purified from a human colon carcinoma xenograft.²⁵ Compared to the original anti-TAG-72 antibody B72.3, CC49 has an affinity constant of about six times higher and has shown a 16-fold increase of tumor/blood ratio in human xenografts in athymic mice.²⁶ On the basis of encouraging preclinical results from Dr. Jeffrey Schlom and colleagues at the National Cancer Institute, ¹³¹I- or ⁹⁰Y-CC49 has been utilized in phase I and II clinical trials at multiple institutions.²⁷

Phase I and II clinical trials of ¹³¹I-CC49 at multiple institutions used a single IV administration of ¹³¹I-CC49 for metastatic GI cancers.^6,28 With 30–90 mCi/m² no objective tumor responses were observed, and limited normal organ and tumor dosimetry was reported. In a high-dose study, patients received a single dose of 1.85–11.1 GBq/m² (50–300 mCi/m²) ¹³¹I-CC49 after collection and cryopreservation of hematopoietic stem cells.⁸ No objective responses were observed with a mean tumor-to-marrow ratio of 4.0 (range 2.5–6.1) in the 5 patients analyzed. Although extrahematopoietic dose-limiting toxicity was neither observed nor predicted, suboptimal tumor uptake (%ID/g ranged 0.0002–0.0021) suggested that further escalation of ¹³¹I-CC49 would not be useful.⁸ In a subsequent high-dose study using long-range beta radiation, patients received a single dose of 11.1–18.5 MBq/kg (0.3–0.5 mCi/kg) ⁹⁰Y-CC49 after collection and cryopreservation of hematopoietic stem cells.⁹ Patient-specific doses for liver, spleen, and tumor based on SPECT imaging, and marrow doses based on radioactivity in the blood were reported.²⁹ Because our current study used the same radionuclides, ⁹⁰Y/¹¹¹In, the difference in tissue dosimetry should be mainly due to the difference in tissue distribution of intact antibody CC49^9,29 and our HuCC49ΔCh2.

The median (range) effective α phase half-life in blood was similar for ⁹⁰Y-CC49 at 3.6 hours (1.1–6.0),²⁹ and ⁹⁰Y-HuCC49ΔCh2 at 3.4 (1.8–5.8). However, the median (range) effective half-life for the β phase was shorter for ⁹⁰Y-HuCC49ΔCh2 at 38 hours (30.5–43.0) compared to 50.0 hours (32.0–63.0) for ⁹⁰Y-CC49. Despite a 30% longer effective β half-life for ⁹⁰Y-CC49, calculated marrow absorbed dose from blood was slightly lower (or comparable) to that of ⁹⁰Y-HuCC49ΔCh2 (Table 5). This apparent discrepancy is due to the difference in absorbed energies in marrow cavity between previous investigators²⁹ based on an early model,³⁰ and the OLINDA/EXM program based on a revised model.³¹ Leichner et al.²⁹ used a fixed RMBLR of 0.3, and we used RMBLR values (0.26–0.33) based on the patient's hematocrit²³; however, the differences in magnitude between these two approaches are not very large, as noted by other investigators.^32,33

Table 5.

Comparison of Median (and Range) Dose Estimates Based on Measured Organ and Tumor Masses Between ⁹⁰ Y-HuCC49 and ⁹⁰ Y-HuCC49ΔCh2

	Radiation dose (Gy/GBq)		Tumor-to-organ dose ratio
Organ or tumor	⁹⁰Y-CC49^a	⁹⁰Y-HuCC49ΔCh2	⁹⁰Y-CC49^a	⁹⁰Y-HuCC49ΔCh2
Liver	7.29 (4.60–21.85)	4.19 (3.19–4.97)	1.00 (0.28–1.54)	3.14 (1.31–8.32)
Spleen	6.87 (3.25–16.89)	5.68 (4.81–8.14)	1.07 (0.46–3.00)	3.19 (1.29–5.12)
Marrow from blood	0.60 (0.44–1.09)	0.87 (0.64–0.97)	9.53 (3.57–42.1)	18.0 (9.70–38.4)
Tumor	7.74 (1.90–21.9)	15.6 (6.2–34.8)

Data from Leichner et al.²⁹ The median (range) effective half-life was 50.0 hours (32.0–63.0) for β phase for ⁹⁰Y-CC49,²⁹ and 38 (30.5–43.0) for β phase for ⁹⁰Y-HuCC49ΔCh2. The absorbed energy for marrow used in Reference 29 was lower than that of OLINDA.

The absorbed dose per injected activity to liver and spleen was smaller for ⁹⁰Y-HuCC49ΔCh2 compared to that of intact CC49 (Table 5), whereas tumor doses were larger for ⁹⁰Y-HuCC49ΔCh2 in this small group of patients. The tumor absorbed dose varied with tumor size, and typically the small tumors had the largest tumor doses. ⁹⁰Y-HuCC49ΔCh2 had higher tumor-to-organ dose ratio for liver, spleen, and marrow compared to ⁹⁰Y-CC49, suggesting an improved therapeutic index for HuCC49ΔCh2 over CC49. The tumor uptake was >5-fold higher in this study than the prior report of ⁹⁰Y-CC49 in similar patients. Although the means for tumor to normal tissue ratios for HuCC49ΔCh2 were improved over those with intact CC49, both ratios had wide ranges in a small number of patients. Comparison dose ratios were used rather than absorbed dose to reduce uncertainties resulting from different imaging techniques.

The shorter blood effective half-life and improved tumor-to-normal tissue ratios with ⁹⁰Y-HuCC49ΔCh2 compared to ⁹⁰Y-CC49 are similar to comparison of ¹³¹I-HuCC49ΔCh2 with ¹³¹I-CC49 in 4 patients previously studied although the parameters compared were not identical. The mean plasma clearance half-life (T_1/2) was shortened from 50 hours for ¹³¹I-CC49 to 20 hours for ¹³¹I-HuCC49ΔCh2.¹² The reported mean whole-body absorbed dose was 0.15 Gy/GBq (0.55 rad/mCi) for ¹³¹I-HuCC49ΔCh2, compared with 0.27 Gy/GBq (1.00 rad/mCi) for murine ¹³¹I-CC49. The reported mean marrow absorbed dose from blood was 0.27 Gy/GBq (1.00 rad/mCi) for ¹³¹I-HuCC49ΔCh2, compared with 0.43 Gy/GBq (1.6 rad/mCi) for murine ¹³¹I-CC49.¹² In small group of patients being reported, ⁹⁰Y-HuCC49ΔCh2 had higher tumor-to-normal organ dose ratio. The reported mean tumor-to-body dose ratio was 13.3 for ¹³¹I-HuCC49ΔCh2,¹² and was 40.2 for ⁹⁰Y-HuCC49ΔCh2. The mean tumor-to-marrow dose ratio was 7.3 for ¹³¹I-HuCC49ΔCh2, and was 21.3 for ⁹⁰Y-HuCC49ΔCh2.

Although minimal amounts of ¹¹¹In and ⁹⁰Y can escape from the chelator, the potential difference in biodistribution of ¹¹¹In-antibody versus ⁹⁰Y-antibody has been well recognized.³⁴ A more accurate marrow absorbed dose estimate for ¹¹¹In/⁹⁰Y could be obtained in the future when bone marrow biopsy data are collected. Marrow absorbed dose can be estimated using direct measurements based on marrow biopsy of individual patients³⁵ or indirect measurements based on combined quantitative imaging and reported marrow biopsy data for that radiopharmaceutical.³⁶

Conclusions

A humanized and CH2 domain-deleted CC49 antibody (IDEC-159) radiolabeled with ¹¹¹In/⁹⁰Y showed about 30% reduction in the blood circulation time compared to the intact CC49 murine antibody. Biodistribution and dosimetry data demonstrated significantly improved tumor-to-normal dose ratios over those reported from studies with intact CC49.

Footnotes

Acknowledgments

The clinical trial was supported by BIOGEN/IDEC Inc. The authors wish to express thanks to Gayle Hines, CNMT, for her excellent work in patient imaging and sample counting, and to Dale Craig, RN, for her excellent work in nursing.

Disclosure Statement

No financial conflict of interest exists for any of the authors.

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Biodistribution and Dosimetry of In-111/Y-90-HuCC49ΔCh2 (IDEC-159) in Patients with Metastatic Colorectal Adenocarcinoma

Abstract

Background:

Materials and Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Patients

111In/90Y- HuCC49ΔCh2 (IDEC-159)

Quantification of 90Y/111In in blood

Quantitative imaging

Organ and tumor volume measurements

Radiation dosimetry with patient-specific organ mass

Results

Quantification of 111In/90Y in blood

Organ and tumor masses

Derived biodistribution of 90Y in organs and tumor

Derived 90Y-HuCC49ΔCh2 dosimetry

Discussion

Conclusions

Footnotes

Acknowledgments

Disclosure Statement

References

¹¹¹In/⁹⁰Y- HuCC49ΔCh2 (IDEC-159)

Quantification of ⁹⁰Y/¹¹¹In in blood

Quantification of ¹¹¹In/⁹⁰Y in blood

Derived biodistribution of ⁹⁰Y in organs and tumor

Derived ⁹⁰Y-HuCC49ΔCh2 dosimetry