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The multicompartmental p32/gClqR as a new target for antibody-based tumor targeting strategies.

ABSTRACT: Tumor-associated cell surface antigens and tumor-associated vascular markers have been used as a target for cancer intervention strategies. However, both types of targets have limitations due to accessibility, low and/or heterogeneous expression, and presence of tumor-associated serum antigen. It has been previously reported that a mitochondrial/cell surface protein, p32/gC1qR, is the receptor for a tumor-homing peptide, LyP-1, which specifically recognizes an epitope in tumor cells, tumor lymphatics, and tumor-associated macrophages/myeloid cells. Using antibody phage technology, we have generated an anti-p32 human monoclonal antibody (2.15). The 2.15 antibody, expressed in single-chain fragment variable and in trimerbody format, was then characterized in vivo using mice grafted subcutaneously with MDA-MB-231 human breast cancers cells, revealing a highly selective tumor uptake. The intratumoral distribution of the antibody was consistent with the expression pattern of p32 in the surface of some clusters of cells. These results demonstrate the potential of p32 for antibody-based tumor targeting strategies and the utility of the 2.15 antibody as targeting moiety for the selective delivery of imaging and therapeutic agents to tumors.

SUBMITTER: Sanchez-Martin D

PROVIDER: S-EPMC3037632 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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The multicompartmental p32/gClqR as a new target for antibody-based tumor targeting strategies.

Sánchez-Martín David D Cuesta Angel M AM Fogal Valentina V Ruoslahti Erkki E Alvarez-Vallina Luis L

The Journal of biological chemistry 20101214 7

Tumor-associated cell surface antigens and tumor-associated vascular markers have been used as a target for cancer intervention strategies. However, both types of targets have limitations due to accessibility, low and/or heterogeneous expression, and presence of tumor-associated serum antigen. It has been previously reported that a mitochondrial/cell surface protein, p32/gC1qR, is the receptor for a tumor-homing peptide, LyP-1, which specifically recognizes an epitope in tumor cells, tumor lymph ...[more]

PMID: 21156793

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Project description:Trigeminal schwannomas (TS), though the second most common intracranial schwannomas, represent only 0.8 to 8% of all Schwannomas. Advancement in imaging and microsurgical techniques has led to a remarkable improvement in the outcome of these benign tumors. Multicompartmental TS, though extensive, have an excellent outcome after surgery. In this article, we present our experience in the management of multicompartmental TS (types middle/posterior [MP], middle/extracranial [ME], and middle/posterior and extracranial [MPE]) and outcome in this rather uncommon group of tumors. This retrospective study included all the cases of multicompartmental TS operated at our institute from 1999 to 2009. The medical data were analyzed retrospectively. The demographic profile, clinical features, radiological findings, management strategies, postoperative complications, length of hospitalization, and outcome were noted. Follow-up data were collected from outpatient department records. The range and average duration of follow-up were noted. There were a total of 43 patients with TS operated over this period. Among them, 4 were type B, 5 type C, 11 type D, 18 type E, and 5 type F. The study included 26 patients (4 type B, 18 type E, and 4 type B). A variety of approaches were used to approach the tumor. Of 26, 23 patients had a gross total or near-total excision while 2 patients were lost to follow-up. Among the three patients who had a near-total excision and follow-up magnetic resonance imaging showed a small residual tumor, two are on close follow-up with no increase in the size of the tumor over a follow-up period of 3 years, the other patient is a 5-year-old boy who is too young for radiosurgery and is on follow-up. There was no mortality while four patients have had fresh permanent postoperative deficits. Multicompartmental TS are a rare, complex but eminently treatable group of tumors. A variety of surgical approaches can be used to excise the tumor. The choice of approach needs to be individualized with total excision providing excellent results.

Project description:BACKGROUND:In the search for novel antibody-drug conjugates (ADCs) with therapeutic potential, it is imperative to identify novel targets to direct the antibody moiety. CD13 seems an attractive ADC target as it shows a differential pattern of expression in a variety of tumors and cell lines and it is internalized upon engagement with a suitable monoclonal antibody. PM050489 is a marine cytotoxic compound tightly binding tubulin and impairing microtubule dynamics which is currently undergoing clinical trials for solid tumors. METHODS:Anti-CD13 monoclonal antibody (mAb) TEA1/8 has been used to prepare a novel ADC, MI130110, by conjugation to the marine compound PM050489. In vitro and in vivo experiments have been carried out to demonstrate the activity and specificity of MI130110. RESULTS:CD13 is readily internalized upon TEA1/8 mAb binding, and the conjugation with PM050489 did not have any effect on the binding or the internalization of the antibody. MI130110 showed remarkable activity and selectivity in vitro on CD13-expressing tumor cells causing the same effects than those described for PM050489, including cell cycle arrest at G2, mitosis with disarrayed and often multipolar spindles consistent with an arrest at metaphase, and induction of cell death. In contrast, none of these toxic effects were observed in CD13-null cell lines incubated with MI130110. Furthermore, in vivo studies showed that MI130110 exhibited excellent antitumor activity in a CD13-positive fibrosarcoma xenograft murine model, with total remissions in a significant number of the treated animals. Mitotic catastrophes, typical of the payload mechanism of action, were also observed in the tumor cells isolated from mice treated with MI130110. In contrast, MI130110 failed to show any activity in a xenograft mouse model of myeloma cells not expressing CD13, thereby corroborating the selectivity of the ADC to its target and its stability in circulation. CONCLUSION:Our results show that MI130110 ADC combines the antitumor potential of the PM050489 payload with the selectivity of the TEA1/8 monoclonal anti-CD13 antibody and confirm the correct intracellular processing of the ADC. These results demonstrate the suitability of CD13 as a novel ADC target and the effectiveness of MI130110 as a promising antitumor therapeutic agent.

Dataset Information

The multicompartmental p32/gClqR as a new target for antibody-based tumor targeting strategies.

Publications

The multicompartmental p32/gClqR as a new target for antibody-based tumor targeting strategies.

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