α- Versus β-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colon Cancer Xenografts

Heskamp, Sandra; Hernandez, Reinier; Molkenboer-Kuenen, Janneke D.M.; Essler, Markus; Bruchertseifer, Frank; Morgenstern, Alfred; Steenbergen, Erik J.; Cai, Weibo; Seidl, Christof; McBride, William J.; Goldenberg, David M.; Boerman, Otto C.

doi:10.2967/jnumed.116.187021

Cited by 36 publications

(35 citation statements)

References 31 publications

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“…Finally, we have established therapeutic activity of α-DOTA-PRIT in models of human colon cancer, breast cancer, or neuroblastoma. Furthermore, these anti-tumor effects were comparable to those achieved with β-DOTA-PRIT, although with much lower levels of administered [ 177 Lu]LuDOTA-Bn radioactivity (for GPA33: 55 MBq/mouse 19 ; for HER2: 167 MBq/mouse 20 ; for GD2: 33 MBq/mouse 17 ), consistent with recently reported preclinical α-therapy studies 41 including α-PRIT 52 , 53 . With pharmacodynamic control of radiotoxic non-tumor-bound [ 225 Ac]Pr, DOTA-PRIT offers a meaningful improvement in the selectivity of α-therapy.…”

Section: Discussionsupporting

confidence: 87%

Alpha radioimmunotherapy using ²²⁵Ac-proteus-DOTA for solid tumors - safety at curative doses

Cheal¹,

McDevitt²,

Santich³

et al. 2020

Theranostics

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This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using 225 Ac and its theranostic pair, 111 In. We call our novel tumor-targeting DOTA-hapten PRIT system “proteus-DOTA” or “Pr.” Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that 225 Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for 177 Lu or 90 Y, leading to poor tumor uptake in vivo . Therefore, we synthesized Pr consisting of an empty DOTA-chelate for 225 Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with 225 Ac and its imaging surrogate, 111 In. In vitro studies verified anti-DOTA scFv recognition of [ 225 Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency. Results: Intravenously (i.v.) administered 225 Ac- or 111 In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [ 225 Ac]Pr and [ 111 In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [ 225 Ac]Pr alone or pretargeted [ 225 Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [ 225 Ac]Pr only ( P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, ...

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Section: Discussionsupporting

confidence: 87%

Alpha radioimmunotherapy using ²²⁵Ac-proteus-DOTA for solid tumors - safety at curative doses

Cheal¹,

McDevitt²,

Santich³

et al. 2020

Theranostics

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“…Liver slices were stained with hematoxylin-eosin. Renal damage was microscopically graded from 0 (no damage) to 4 (severe damage) by an experienced pathologist, according to Supplementary Table 10 12 .…”

Section: Methodsmentioning

confidence: 99%

Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice

et al. 2018

Self Cite

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Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.

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“…85 Another effective pretargeting strategy uses a trivalent bsAb with 2 target-specific Fabs and an anti-histamine-succinyl-glycine (HSG) Fab, and the 3 arms of this Tri-Fab (TF) are linked by disulfide bonds. Example targets for bispecific antibody pretargeting include CD105 and EGFR, 46 CEA, 86,87 and TROP2. 88…”

Section: Bispecific Antibodies For Pretargetingmentioning

confidence: 99%

“…TF2 was used for pretargeted radioimmunotherapy (PRIT) in mice bearing CEA-positive colorectal cancer xenografts, where alpha-emitting hapten 213 Bi-IMP288 was shown to be at least as effective as beta-emitting hapten 177 Lu-IMP288. 86 Tri-Fab pretargeting was extended to the target trophoblast cell surface antigen 2 (TROP2), a transmembrane protein overexpressed in numerous cancers. TF12 is composed of 2 anti-TROP2 Fabs, along with one anti-HSG Fab that allows for the substitution of a radiolabeled hapten-peptide, IMP-288.…”

Section: Bispecific Antibodies For Pretargetingmentioning

confidence: 99%

Aligning physics and physiology: Engineering antibodies for radionuclide delivery

Tsai

2018

Labelled Comp Radiopharmac

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The exquisite specificity of antibodies and antibody fragments renders them excellent agents for targeted delivery of radionuclides. Radiolabeled antibodies and fragments have been successfully used for molecular imaging and radioimmunotherapy (RIT) of cell surface targets in oncology and immunology. Protein engineering has been used for antibody humanization essential for clinical applications, as well as optimization of important characteristics including pharmacokinetics, biodistribution, and clearance. Although intact antibodies have high potential as imaging and therapeutic agents, challenges include long circulation time in blood, which leads to later imaging time points post-injection and higher blood absorbed dose that may be disadvantageous for RIT. Using engineered fragments may address these challenges, as size reduction and removal of Fc function decreases serum half-life. Radiolabeled fragments and pretargeting strategies can result in high contrast images within hours to days, and a reduction of RIT toxicity in normal tissues. Additionally, fragments can be engineered to direct hepatic or renal clearance, which may be chosen based on the application and disease setting. This review discusses aligning the physical properties of radionuclides (positron, gamma, beta, alpha, and Auger emitters) with antibodies and fragments and highlights recent advances of engineered antibodies and fragments in preclinical and clinical development for imaging and therapy.

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α- Versus β-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colon Cancer Xenografts

Cited by 36 publications

References 31 publications

Alpha radioimmunotherapy using ²²⁵Ac-proteus-DOTA for solid tumors - safety at curative doses

Alpha radioimmunotherapy using ²²⁵Ac-proteus-DOTA for solid tumors - safety at curative doses

Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice

Aligning physics and physiology: Engineering antibodies for radionuclide delivery

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α- Versus β-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colon Cancer Xenografts

Cited by 36 publications

References 31 publications

Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses

Alpha radioimmunotherapy using 225Ac-proteus-DOTA for solid tumors - safety at curative doses

Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice

Aligning physics and physiology: Engineering antibodies for radionuclide delivery

Contact Info

Product

Resources

About

Alpha radioimmunotherapy using ²²⁵Ac-proteus-DOTA for solid tumors - safety at curative doses

Alpha radioimmunotherapy using ²²⁵Ac-proteus-DOTA for solid tumors - safety at curative doses