Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study

Renata Pasqualini, Randall E Millikan, Dawn R Christianson, Marina Cardó-Vila, Wouter H P Driessen, Ricardo J Giordano, Amin Hajitou, Anh G Hoang, Sijin Wen, Kirstin F Barnhart, Wallace B Baze, Valerie D Marcott, David H Hawke, Kim-Anh Do, Nora M Navone, Eleni Efstathiou, Patricia Troncoso, Roy R Lobb, Christopher J Logothetis, Wadih Arap, Renata Pasqualini, Randall E Millikan, Dawn R Christianson, Marina Cardó-Vila, Wouter H P Driessen, Ricardo J Giordano, Amin Hajitou, Anh G Hoang, Sijin Wen, Kirstin F Barnhart, Wallace B Baze, Valerie D Marcott, David H Hawke, Kim-Anh Do, Nora M Navone, Eleni Efstathiou, Patricia Troncoso, Roy R Lobb, Christopher J Logothetis, Wadih Arap

Abstract

Background: Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature.

Methods: The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer.

Results: BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine.

Conclusions: These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients.

Keywords: bone metastasis-targeting peptidomimetic-11; clinical trial; interleukin-11 receptor α; prostate cancer; vascular targeting.

© 2015 American Cancer Society.

Figures

Figure 1
Figure 1
The efficacy of bone metastasis-targeting peptidomimetic-11 (BMTP-11) was investigated in tumor-bearing, immunodeficient mouse models of prostate cancer. (A) DU145-derived, tumor-bearing nu/nu (nude) mice were treated with either BMTP-11 (10 mg/kg; n = 10) or saline (control; n = 10) intravenously through the tail vein once weekly for 4 weeks. Tumor growth was serially monitored, and tumor volumes were measured over time. Data shown are the means ± standard error of the means (SEM). (B) In a mixed-effects model, there was a significant difference over time in the average percentage change from baseline for tumor volume in the treated animals versus the control animals (P < .0001). (C) Tumor volumes on day zero (pretreatment) and on day 28 (post-treatment) are illustrated. (D) LNCaP-derived, tumor-bearing nude mice were treated with either BMTP-11 (15 mg/kg; n = 4) or saline (control; n = 4) intravenously 3 times weekly for 2 weeks. Tumor growth was serially monitored, and tumor volumes were measured over time. Data shown are the means ± SEM. (E) In a mixed-effects model, there was a significant difference over time in the average percentage change from baseline for tumor volume in the treated animals versus the control animals (P < .0001). (F) Tumor volumes on day zero (pretreatment) and on day 28 (post-treatment) are illustrated. (G) (Top Right) The expression of interleukin-11 receptor alpha (IL-11Rα) is observed in MDA-PCA-118b–implanted tumors (T) relative to (Bottom Right) an immunoglobulin G (IgG) isotype-negative control. The asterisk indicates bone. (Top Left) Anti-CD31 (cluster of differentiation 31 [also called platelet endothelial cell adhesion molecule]) and (Bottom Left) hematoxylin and eosin (H&E) stains also are shown. (H) Severe combined immunodeficient (SCID) mice bearing MDA-PCA-118b–implanted tumors were divided into equal pretreatment cohorts using x-ray imaging, and (I) the bone-to-tumor stroma ratio was quantified in each group using relative mean gray-scale analysis before treatment was initiated. (J) MDA-PCA-118b tumor-bearing SCID mice were treated with either BMTP-11 (10 mg/kg; n = 5) or saline (control; n = 5) intravenously through the tail vein once weekly for 3 weeks. Tumor growth was serially monitored, and volumes were measured over time. Data shown are the means ± SEM. (K) In a mixed-effects model, there was a significant difference over time in the average percentage change from baseline for tumor volume in the treated animals versus the control animals (P < .0001). (L) Tumor volumes on day zero (pretreatment) and on day 21 (post-treatment) are illustrated.
Figure 2
Figure 2
Bone metastasis-targeting peptidomimetic-11 (BMTP-11) pharmacokinetics and metabolites in nonhuman primates are illustrated, including (A) the BMTP-11 standard curve in the plasma of cynomolgus monkeys and (B) the BMTP-11 plasma concentration time curves after intravenous infusion of BMTP-11 (at doses of 1 mg/kg, 3 mg/kg, and 9 mg/kg) for 2 hours. (C) This is a dose-linearity plot for the 3 different BMTP-11 doses. AUC indicates the area under the plasma concentration-time curve. (D) Observed values and model prediction fitted to a 1-compartment, open-body model (constructed using Phoenix WinNonlin [Certara LP, Princeton, NJ]) are shown. (E) Identified metabolites of BMTP-11 in plasma and their predicted amino acid sequence were based on molecular mass. The boxed top sequence indicates the parent drug, BMTP-11 (peak 2483 [p2483]). S-S indicates disulfide bonds.
Figure 3
Figure 3
Photomicrographs illustrate the expression of interleukin-11 receptor alpha (IL-11Rα) and negative control (immunoglobulin G [IgG] isotype) in human bone marrow. Each patient from the treated cohort (n = 6) underwent a bone marrow biopsy before receiving bone metastasis-targeting peptidomimetic-11.
Figure 4
Figure 4
Bone metastasis-targeting peptidomimetic-11 (BMTP-11) targets bone metastasis in patients with castrate-resistant prostate cancer. (A) This is the scheme for the first-in-man clinical trial design. GLP indicates good laboratory practice; IVPB, intravenous piggy-back infusion. (B) BMTP-11 detection by mass spectrometry is illustrated, including (Left) the cleaved proapoptotic domain and (Right) the parent BMTP-11 compound. (C) BMTP-11 immunocolocalization and (D) the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay are shown before and after treatment with BMTP-11 (18 mg/m2) in representative patient samples.
Figure 5
Figure 5
Serial changes in serum tumor markers are illustrated in a patient before and after treatment with bone metastasis-targeting peptidomimetic-11 (BMTP-11). Serum prostate-specific antigen (PSA), alkaline phosphatase (Alk. Phos.), and lactate dehydrogenase (LDH) levels are indicated. 5-FU indicates infusional 5-fluorouracil plus concomitant external-beam radiotherapy; CVD, intravenous cyclophosphamide and vincristine plus oral dexamethasone; DES/Dex, oral diethylstilbestrol plus oral dexamethasone; G/S, gemcitabine intravenously plus oral sunitinib; KA/VE, oral ketoconazole plus doxorubicin intravenously alternating on a weekly basis with oral estramustine plus vinblastine intravenously; T/C, paclitaxel plus carboplatin intravenously every 3 weeks; T/S, docetaxel intravenously plus oral sunitinib; VP-16/CDDP, etoposide plus cisplatin intravenously every 3 weeks.

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Source: PubMed

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