A humanised anti-IGF-1R monoclonal antibody (AVE1642) enhances Bortezomib-induced apoptosis in myeloma cells lacking CD45

Abstract

The humanised form of an antagonistic anti-IGF-1R mAb (AVE1642) selectively inhibits the growth of CD45 neg myeloma cells. AVE1642 strongly increased bortezomib-induced apoptosis, correlated with an increase of Noxa expression. These results support the therapeutic use of anti-IGF-1R/bortezomib in CD45 neg Myeloma patients, particularly those with the most aggressive form, t(4,14).

Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma

“…We have previously shown that AVE1642 was able to inhibit the proliferation of CD221 positive-CD45 negative, but not that of CD221 positive-CD45 positive human myeloma cell lines, and that the overexpression of CD221 in CD45-positive human myeloma cell lines was not sufficient to induce AVE1642 sensitivity. 4,8 On the contrary, extinction of CD45 by shRNA in CD45 positive human myeloma cell lines was able to induce AVE1642 sensitivity. In the present study, CD45 phenotype was evaluated in 23 out of 26 patients, and was negative in 16 cases (70%).…”

“…AVE1642 has been able to delay growth and survival of some cancer cells in vitro, human tumor xenografts in nude mice, and to inhibit proliferation and survival of most MM cells (primary cells from patients or MM cell lines). 4 The present phase 1, multicenter, 2-part study, open-label, was to explore the dose to be selected for further development of AVE1642 (dose escalation design, part 1), to evaluate pharmacokinetics (clearance of the antibody) and pharmacodynamics (IGF-1 serum levels) of AVE1642 alone and in combination with bortezomib, and to assess the safety of the combination of AVE1642 (at the selected dose), with the recommended dose of bortezomib in patients with relapsed MM (Part 2).…”

“…4 AVE1642 is a humanized version of the murine monoclonal antibody, EM164, raised against the human IGF-1R. 5 It has been shown to bind specifically, with a high affinity, to human and monkey IGF-1R, to inhibit IGF-1 binding and receptor activation, and to downregulate the receptor by internalization and degradation.…”

Targeting Human Cancer Stem Cells with Monoclonal Antibodies

“…AVE1642 inhibits growth and increases bortezomib-induced apoptosis of aggressive human myeloma cells in vitro [159]. Based on these results, a phase I clinical study of AVE1642 in combination with the proteasome inhibitor bortezomib was conducted in patients with relapsed multiple myeloma.…”

Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma

“…60 The mechanism of synergy between AVE1642 and bortezomib may be related to synergistic upregulation of Noxa, which induces the release of the BH3-only activators that are responsible for Bax activation. 60 On the basis of these results and phase 1 data, which showed good tolerability of AVE1642 in advanced myeloma (except for grade 3 hyperglycemia in diabetic patients), 61 the combination of AVE1642 and bortezomib was tested in relapsed/refractory myeloma. Although this combination was well tolerated, response rate was low with at least PR in only 18% of patients.…”