Abstract 4576: IMGN853, an anti-Folate Receptor I antibody-maytansinoid conjugate for targeted cancer therapy

Abstract

Previously we reported (O. Ab; EORTC, 2010) that an antibody-maytansinoid conjugate (AMC) composed of an anti-FOLR1 antibody conjugated to the cytotoxic maytansinoid, DM4, via the disulfide-containing linker, SPDB, was potent in killing FOLR1-expressing cancer cells in vitro and in vivo. In light of the favorable results noted, we assessed the optimal antibody, linker, and maytansinoid agent for an AMC targeting FOLR1, as reported here. Antibody selection. Anti-FOLR1 antibodies were generated by immunizing mice with human FOLR1-expressing cells, and a panel of FOLR1-specific antibodies was identified by flow cytometry binding assay. Several FOLR1-antibodies with high binding affinity to both human and monkey FOLR1 were chosen for further evaluation and were humanized using ImmunoGen's resurfacing technology. Antibodies were conjugated to DM1 via the non-cleavable SMCC linker and the conjugates tested for activity against FOLR1-positive KB cells in vitro and in vivo. All conjugates had comparable cytotoxic potencies in vitro. However, the in vivo anti-tumor activity of one conjugate, M9346A-SMCC-DM1, was significantly better than that of SMCC-DM1 conjugates of other FOLR1 antibodies. Based on this finding, the M9346A antibody was chosen for further development. Linker/maytansinoid selection. The M9346A antibody was linked to DM1 or DM4 via the disulfide-containing cleavable linkers SPP, SPDB or sulfo-SPDB, or via the non-cleavable SMCC linker. We compared the in vitro cytotoxic activities of these conjugates on KB, Igrov-1 and Jeg-3 cell lines. The conjugates with cleavable linkers displayed markedly greater in vitro activities than the SMCC conjugate. We then examined the in vivo activities of the conjugates in FOLR1-positive KB- and Ovcar 3-tumor models. Again, we found that the conjugates with cleavable linkers were more active in vivo than the noncleavable conjugate. Among the conjugates with cleavable linkers, the sulfo-SPDB-DM4 conjugate was the most active conjugate against the Ovcar-3 model, it had activity comparable to that of the SPDB-DM4 conjugate against KB tumors, and both were more active than the SPP-DM1 conjugate in the two xenograft models. Taking into consideration that sulfo-SPDB-DM4 was the most efficacious design in vivo and the potential of the hydrophilic sulfo-SPDB-linker to enable better activity against PgP-expressing cells (previously reported data), M9346A-sulfo-SPDB-DM4 was selected to be the candidate for development and designated IMGN853. IMGN853 is a promising candidate for the treatment of FOLR1-expressing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4576. doi:10.1158/1538-7445.AM2011-4576

Drug‐conjugated antibodies for the treatment of cancer

“…Other maytansinoid ADCs that are in early phase I clinical evaluation, and which utilize the SPDB linker for conjugation of DM4, include SAR566658, a conjugate with the anti‐CA6 antigen, a tumour‐associated glycotope of Muc‐1 that is expressed on ovarian, breast, cervical, lung and pancreatic cancers , and BAY 94–9343, a conjugate of an anti‐mesothelin antibody that targets mesothelioma, ovarian and pancreatic cancers . In early 2012, phase I evaluation of IMGN529, an anti‐CD37 humanized IgG1 antibody conjugated to DM1 via the uncleavable SMCC linker , was initiated in patients with NHL, and recently, a phase I trial was begun with IMGN853, an anti‐FOLR1 humanized IgG1 antibody conjugated to DM4 using a novel hydrophilic disulfide linker .…”

Antikörper‐Wirkstoff‐Konjugate: ein neues Konzept in der Krebstherapie

“…Die In-vitro-Wirksamkeit von AMCs aus einem Antikçrper gegen den Folatrezeptor a (anti-FOLR1) verdeutlicht diesen Befund (Abbildung 11). [58] Die anti-FOLR1-Konjugate mit den Thioether-oder Disulfid-Linkern hatten vergleichbare In-vitro-Wirksamkeit auf antigen-positive KB-Zellen, die mindestens 2 10 6 Rezeptoren pro Zelle exprimieren. Konjugate mit Disulfid-Linkern waren allerdings wirksamer als AMCs mit Thioether-Linkern gegenüber JEG-3-Zellen, die das Zielantigen nur etwa 4 10 4 -mal pro Zelle exprimieren.…”

“…Konjugate mit Disulfid-Linkern waren allerdings wirksamer als AMCs mit Thioether-Linkern gegenüber JEG-3-Zellen, die das Zielantigen nur etwa 4 10 4 -mal pro Zelle exprimieren. [58] Der Wirksamkeitsunterschied von Disulfid-im Vergleich zu Thioether-verbrückten anti-FOLR1-AMCs scheint also von der Zelllinie oder der Expressionshçhe des Antigens abzuhängen. EGFR-AMCs mit einem Disulfid-und einem Thioether-Linker waren vergleichbar wirksam gegenüber MDA-MB-468-Zellen, während die disulfidverbrückte Verbindung gegenüber A-431-Zellen mehr als 20-mal wirksamer war, obwohl in diesem Fall die Hçhe der Antigenexpression vergleichbar war.…”

Fourth World Antibody-Drug Conjugate Summit

“…To identify an optimal antibody for payload delivery for this target, large numbers of anti-FOLR1 antibodies were screened for their ability to deliver maytansinoid using an indirect assay. Direct maytansinoid conjugates of candidate antibodies that emerged from the indirect screen were prepared, and a lead antibody selected based on its superior efficacy as a conjugate against tumor xenograft models 49 . The conjugate design was optimized by evaluating different linker-maytansinoid formats.…”

“…Direct maytansinoid conjugates of candidate antibodies that emerged from the indirect screen were prepared, and a lead antibody selected based on its superior efficacy as a conjugate against tumor xenograft models. 49 The conjugate design was optimized by evaluating different linker-maytansinoid formats. A conjugate incorporating a novel hydrophilic disulfide (cleavable) linker, sulfo-SPDB, was found to be the most active in vivo, and was designated as development candidate IMGN853.…”