New Linkers for MDR Cancers

We have recently disclosed to our existing partners that we have filed patent applications for a new generation of linkers particularly well suited for multi-drug resistant (MDR) cancers. These linkers also offer potential for conjugates against cancers that express the target antigen at low density. We are starting to present on these linkers at scientific conferences and also wanted to use this opportunity to make companies that are not currently our partners aware of this innovation.

Our new hydrophilic (POL) linkers can be used to attach our maytansinoid cell-killing agents (DMx) using either reducible or non-reducible bonds (“cleavable” and “non-cleavable” bonds, respectively). Like our other linkers, they remain intact while the antibody-DMx conjugate is circulating in the bloodstream and enable the DMx to exert its full potency once inside a cancer cell.

The enhanced activity of these new linkers against MDR cells can be seen in studies we conducted with EpCAM-targeting conjugates. EpCam is expressed on HCT15, a human colon carcinoma cell line with naturally evolved MDR. It also is expressed on the human colon carcinoma cell line, COLO 205, and on COLO 205-MDR, which is a COLO 205 clone engineered to over-express P-glycoprotein (Pgp). Pgp is one of the best studied mediators of MDR.

We made conjugates using a monoclonal antibody (MAb) that binds to EpCAM with: a reducible disulfide linker (MAb-SPDB-DM4), the non-reducible linker (MAb-MCC-DM1) used in trastuzumab-DM1, and one of our new hydrophilic linkers (MAb-POL-DM1).

In vitro, all three conjugate designs demonstrated similar, pronounced activity against standard (non-MDR) COLO 205 human cancer cells:

There was, however, a marked difference in the activity of the conjugates against the MDR resistant COLO 205 cell line, with the MAb-POL-DM1 conjugate demonstrating significantly greater activity against COLO 205-MDR than either of the other two designs:

The MAb-POL-DM1 conjugate also demonstrated significantly greater activity in vitro against the HCT15 MDR cell line than either of the other two designs:

All three conjugates were found to have similar potency in the presence of Cyclosporin A, an inhibitor of Pgp. This result suggests that the improved potency of the POL conjugate pertains to its ability to inhibit the Pgp efflux pump, and thus the pumping of the DMx species out of the cancer cell.

The results seen against MDR cell lines in vitro also were seen in vivo. That is, the MAb-POL-DM1 conjugate was found to be more active against both MDR cell lines in xenograft models in SCID mice than the SPDB or SMCC conjugates.

ImmunoGen’s new hydrophilic linkers provide enhanced potency against multi-drug resistant cancers. These linkers thus extend the reach of ImmunoGen’s maytansinoid technology to cancers known to commonly become multi-drug resistant.

Companies interested in obtaining additional information on our linker and cell-killing agent technology portfolio should contact our Business Development department.