Preclinical Targeted α- and β--Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies

Janik Puttemans, Yana Dekempeneer, Jos L Eersels, Heleen Hanssens, Pieterjan Debie, Marleen Keyaerts, Albert D Windhorst, Frank van der Aa, Quentin Lecocq, Karine Breckpot, Alfred Morgenstern, Frank Bruchertseifer, Tony Lahoutte, Nick Devoogdt, Matthias D'Huyvetter, Janik Puttemans, Yana Dekempeneer, Jos L Eersels, Heleen Hanssens, Pieterjan Debie, Marleen Keyaerts, Albert D Windhorst, Frank van der Aa, Quentin Lecocq, Karine Breckpot, Alfred Morgenstern, Frank Bruchertseifer, Tony Lahoutte, Nick Devoogdt, Matthias D'Huyvetter

Abstract

HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and treating cancerous lesions in vivo using different radiolabeling methods. Here we evaluate the anti-HER2 sdAb 2Rs15d, coupled to diagnostic γ- and therapeutic α- and β--emitting radionuclides for the detection and treatment of HER2pos brain lesions in a preclinical setting. 2Rs15d was radiolabeled with 111In, 225Ac and 131I using DTPA- and DOTA-based bifunctional chelators and Sn-precursor of SGMIB respectively and evaluated in orthotopic tumor-bearing athymic nude mice. Therapeutic efficacy as well as systemic toxicity were determined for 131I- and 225Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2pos tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2pos SK-OV-3-Luc-IP1 and HER2pos MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [131I]-2Rs15d and [225Ac]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone. Histopathological analysis revealed no significant early toxicity. Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. These data demonstrate the potential of radiolabeled sdAbs as a valuable add-on treatment option for patients with difficult-to-treat HER2pos metastatic cancer.

Keywords: HER2; brain metastasis; single-domain antibody fragment; targeted radionuclide therapy.

Conflict of interest statement

J.E. is an employee of Camel-IDS. M.D., N.D. and T.L. are employees or consultants of Camel-IDS and hold ownership interest (including patents) in sdAb radiotherapeutics. T.L. is member of the scientific advisory board of Ion Beam Applications (IBA) and member of the strategic committee of the Institute of RadioElements (IRE). M.K. received travel and accommodation expenses from Bayer, research funding from Camel-IDS and holds patents on sdAb imaging and therapy. All other authors have declared no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
In vitro trastuzumab-mediated growth inhibition of (A) SKOV3.IP1 cells, naturally expressing high HER2 levels and (B) 231Br cells, stably transfected to express high levels of HER2. Cells were cultured with different trastuzumab concentrations from day 0–5, followed by trastuzumab-free medium at day 6–10. Concentration-dependent growth inhibition can be observed for SKOV3.IP1 cells during trastuzumab treatment. 231Br cell growth was not hampered, regardless of trastuzumab concentration. (ns: not significant, ** p < 0.01, *** p < 0.005).
Figure 2
Figure 2
(A) Follow-up of SKOV3.IP1 an 231Br tumor growth in function of time using body weight measurements, and (B) quantitative (photons/s/cm2/steradian) and (C) visual in vivo bioluminescence imaging at day 3, 7, 10, 14, 17 and 21 post-inoculation (images shown of SKOV3.IP1 tumors and are representative for both tumor models). Values are presented as mean ± SD.
Figure 3
Figure 3
Ex vivo biodistribution of radiolabeled anti-HER2 tracers in brain tumor-bearing mice. (A) Ex vivo biodistribution analyses of [111In]-labeled compounds in HER2pos tumor-bearing mice, at 1 h p.i. (sdAbs) and 3 d p.i. (mAb) (n = 4). For sdAbs only kidneys show elevated uptake, whereas trastuzumab has increased tracer uptake in all highly vascularized organs. Detail of tracer uptake in tumor, brain and blood shows a significantly higher tumor uptake for [111In]-2Rs15d in (B) SKOV3.IP1 and (C) 231Br brain tumors compared to the non-targeting [111In]-R3B23. Increased tumor-to-brain ratio of [111In]-trastuzumab was only observed in 231Br tumors (C). (ns: not significant, ** p < 0.01, *** p < 0.005, **** p < 0.001).
Figure 4
Figure 4
Sagittal view of fused whole-body and brain-focused µSPECT/CT scan images of anti-HER2 [111In]-2Rs15d, non-targeting [111In]-R3B23 and anti-HER2 [111In]-trastuzumab 1 h and 3 days p.i. in SKOV3.IP1 (Left) and 231Br (Right) tumor models. One representative image of each group (n = 4) is shown. Tumor-targeting is visible for [111In]-2Rs15d in both tumor models, whereas [111In]-trastuzumab was only able to accumulate in 231Br tumors. High uptake was also observed in highly vascularized organs up to 3 days after injection. There was no aspecific leakage of non-targeting [111In]-R3B23 into the tumor site. T: tumor, Bl: blood, K: kidney, H: heart, L: liver, B: bladder, TB: total body, BF: brain focus.
Figure 5
Figure 5
Event-free survival during TRNT. Events were defined as (i) mortality, (ii) weight loss > 20%, (iii) immobility, (iv) unresponsiveness to external stimuli. 231Br tumor-bearing mice (n = 8 per group, tumor inoculation on Day 0) were treated with intravenous injections of [131I]-2Rs15d (Day 7, 14), combination treatment of [131I]-2Rs15d (Day 7, 14) and trastuzumab (Loading dose; day 7-maintenance dose; day 10, 14, 17, 21, 24, 28) or trastuzumab as single agent (Loading dose; day 7-maintenance dose; day 10, 14, 17, 21, 24, 28). Control groups received either vehicle buffer or unlabeled 2Rs15d in equimolar quantities as treated groups at identical timepoints (A). 231Br tumor-bearing mice (n = 3, tumor inoculation on Day 0) received [131I]-2Rs15d (Day 7, 14), followed by µSPECT/CT imaging 2 h p.i. Fused µSPECT/CT images (B) and image quantification (C) showed accumulation of activity in brain tumor, thyroid and kidneys. Trast: Trastuzumab, T: tumor, K: kidney, Th: thyroid, TB: total body, BF: brain focus (ns: not significant, * p < 0.05).
Figure 6
Figure 6
Event-free survival during targeted alpha therapy. Events were defined as (i) mortality, (ii) weight loss > 20%, (iii) immobility, (iv) unresponsiveness to external stimuli. Trastuzumab-sensitive SKOV3.IP1 (A) and trastuzumab-resistant 231Br (B) tumor-bearing mice (n = 8 per group, tumor inoculation on Day 0) were treated with intravenous injections of either [225Ac]-2Rs15d (Day 7, 10, 14), combination treatment of [225Ac]-2Rs15d (Day 7, 14, 21) and trastuzumab (Loading dose; day 7-maintenance dose; day 10, 14, 17, 21, 24, 28) or trastuzumab as single agent (Loading dose; day 7-maintenance dose; day 10, 14, 17, 21, 24, 28). The control group received vehicle buffer at identical timepoints as treated groups. 150 mg/kg gelofusin was co-administered with [225Ac]-2Rs15d in order to reduce kidney retention. (ns: not significant, * p < 0.05, ** p < 0.01, *** p < 0.005).

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