Compositions and Methods for Treatment of Ovarian Cancer
A kind of composition and compound technology, applied in the composition and field of treating ovarian cancer
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[0043] The preparation of different versions of humanized N901 has been described, see Roguska et al., Proc. 1996), the disclosure of which is incorporated by reference in its entirety. To denote humanized antibodies, the letters "hu" or "h" appear before the antibody name. For example, humanized N901 can be referred to as huN901 or hN901.
[0044] IMGN901 is an antibody-drug conjugate (ADC) comprising the CD56-binding monoclonal antibody, huN901, and a maytansinoid cytotoxic agent and DM1. See Example 1 in US Patent No. 7,303,749 for an exemplary description of the huN901 / DM1 conjugate. Said US Patent No. 7,303,749 (Inventor: R.V.J. Chari; issued December 4, 2007) is hereby incorporated by reference in its entirety. Information on other maytansinoid compounds is also discussed further herein.
[0045] IMGN901 binds with high affinity to CD56 expressed on the surface of tumor cells. Once bound, the conjugate is internalized and the DM1 is released.
[0046] DM1 is an ant...
Embodiment approach
[0104] In one embodiment, the cytotoxic compound is linked to the cell-binding agent through a disulfide bond or a thioether bond. The linker molecules comprise reactive chemical groups that can react with cell binding reagents. Exemplary reactive chemical groups reactive with cell binding reagents are N-succinimide esters and N-sulfosuccinimide esters. In addition, the linker molecule can include a reactive chemical group, such as a dithiopyridyl group, which can react with the drug to form a disulfide bond. Detailed embodiments of linker molecules including, for example, N-succinimidyl 3-(2-dithiopyridyl)propionate (SPDP) (see, for example, Carlsson et al., Biochem. J., 173:723-737 (1978)), N-succinimidyl 4-(2-dithiopyridyl) butyrate (SPDB) (see, e.g., U.S. Patent 4,563,304), N-succinimidyl 4-(2-bis Thiopyridyl)pentanoate (SPP) (see, eg, CAS Registry number 341498-08-6), and other reactive crosslinkers, described in US Patent 6,913,748.
[0105] Embodiments of the inventi...
Embodiment 1
[0165] Example 1. Antitumor Activity of IMGN901 in the Treatment of OVCAR-3 Human Ovarian Cancer Xenograft Model
[0166] The antitumor activity of the IMGN901 was evaluated in an established subcutaneous xenograft model of ovarian cancer. SCID mice were inoculated with OVCAR-3 ovarian cancer cells (1x10 7 cells / animal), injected subcutaneously into the right flank. When the tumor reaches about 100mm 3 Size (24 days after tumor inoculation), the mice were randomly divided into three groups (6 animals per group). Mice were treated with a single agent, IMGN901, at 6.5 mg / kg and 13 mg / kg, respectively, administered intravenously once a week for 3 weeks (days 24, 31, 39). Control animals received PBS intravenously on the same schedule. Tumor growth was monitored by measuring tumor size twice weekly. Tumor size was calculated according to the following general formula: length × width × height × 1 / 2 .
[0167] figure 1 .IMGN901 was active against OVCAR-3 tumors in terms ...
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