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In vitro binding evaluation of 177Lu-AMBA, a novel 177Lu-labeled GRP-R agonist for systemic radiotherapy in human tissues

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Abstract

Members of the gastrin-releasing peptide (GRP) family and its analogs bombesin (BBN) have been implicated in the biology of several human cancers including prostate, breast, colon and lung. To date, three mammalian GRP/BBN receptor subtypes have been cloned and characterized: the neuromedin B receptor (NMBR), the GRP receptor (GRPR) and the BBN-receptor subtype 3 (BB3). The fourth BBN receptor subtype, BB4, has only been identified in amphibian and at present no mammalian equivalent of this receptor has been described. GRPR analogs have been used as carriers to deliver drugs, radionuclides and cytotoxins to target various cancer types that are GRPR positive. We investigated the in vitro binding properties of 177Lu-AMBA, a novel radiolabelled BBN analog currently undergoing clinical trial as systemic radiotherapy for hormone refractory prostate cancer (HRPC) patients. Pharmacological analyses of the 177Lu-AMBA was determined using in vitro binding studies using membrane target system containing specific receptor subtypes. We investigated the distribution of binding sites for 177Lu-AMBA by receptor autoradiography on human neoplastic and non-neoplastic tissues. Pharmacological characterizations of 177Lu-AMBA shows, high affinity towards NMB and GRP receptors, while little or no affinity towards BB3 receptor. Among the 40 different types of non-neoplastic tissues tested seven of them showed limited but specific binding of 177Lu-AMBA. Fourteen of 17 primary prostate cancers, six of 13 primary breast cancers expressed binding sites for 177Lu-AMBA. Furthermore, no apparent differences in 177Lu-AMBA-binding sites expression were observed between matched pairs (primary vs. secondary) of prostate and breast cancer tissues. These data represent the molecular basis for clinical applications of 177Lu-AMBA for diagnosis and treatment of GRP-R and NMB-R positive tumors.

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Abbreviations

GRP-R:

Gastrin Releasing Peptide receptor

NMB-R:

Neuromedin B Receptor

SST:

Somatostatin

BBN:

Bombesin

AMBA:

DO3A10CM-CH2CO-G-4-aminobenzoyl-BBN7–14

ARG:

Autoradiography

IDC:

Invasive ductal carcinoma

ILC:

Invasive lobular carcinoma

PIN:

Prostatic intra epithelial Neoplasia

HRPC:

Hormone refractory prostate cancer

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Authors and Affiliations

  1. Discovery Biology, Ernst Felder Laboratories, Bracco Research USA, Princeton, NJ, 08540, USA

    Regi Thomas, Laura E. Lantry & Adrian D. Nunn

  2. Discovery Chemistry, Ernst Felder Laboratories, Bracco Research USA, Princeton, NJ, USA

    Jianqing Chen

  3. Department of Urology, University of Washington, Seattle, WA, USA

    Martine M. Roudier & Robert L. Vessella

  4. Department of Pathology, University of Washington, Seattle, WA, USA

    Martine M. Roudier

  5. Department of Pathology, Amgen Washington, Seattle, WA, USA

    Martine M. Roudier

  6. Puget Sound VA Health Care System, Seattle, WA, USA

    Robert L. Vessella

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  1. Regi Thomas
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Correspondence to Regi Thomas.

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Thomas, R., Chen, J., Roudier, M.M. et al. In vitro binding evaluation of 177Lu-AMBA, a novel 177Lu-labeled GRP-R agonist for systemic radiotherapy in human tissues. Clin Exp Metastasis 26, 105–119 (2009). https://doi.org/10.1007/s10585-008-9220-0

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