Chemistry Reference
In-Depth Information
explored at the same time, showed that a single linker-cytotoxic agent com-
bination was not necessarily the best for all antibodies, and that considerations
need to be made as to the antigen being targeted and the properties of cells
expressing that antigen.
Gemtuzumab ozogamicin was probably the easiest of all possible calichea-
micin conjugates to start clinical investigations with, even though other con-
jugates have failed in this setting.
62
The target cells are readily accessible from
circulation and they are known to be prone to apoptosis induced by DNA
damage. However, clinical experience with this conjugate has amply demon-
strated some of the pitfalls that can be encountered in conjugate development.
Although a relatively high proportion of the conjugate binds to target cells, the
toxicities of traditional chemotherapy are not altogether avoided, even though
there is significant improvement. The response rate is quite meaningful, but less
than 100% due to various resistance mechanisms, such as Pgp and resistance to
apoptosis, likely making combination therapy the ultimate best use of gemtu-
zumab ozogamicin. Much more remains to be learned in on-going and future
clinical trials, with the obvious goal of discerning the optimal use of gemtu-
zumab ozogamicin in all stages of AML, especially first indication.
As to the other applications of calicheamicin conjugates, inotuzumab ozo-
gamicin (CMC-544), which targets the CD22 antigen, has advanced to Phase 3
clinical trials for non-Hodgkin's lymphoma; considering some of the simila-
rities of these hematopoietic malignancies, it is reasonable to expect that ino-
tuzumab ozogamicin would be successful, although the target cells are not as
accessible as leukemic cells. The next obvious goal for calicheamicin conjugates
is activity against solid tumors. CMB-401 failed in two small Phase 2 trials,
possibly due to shed antigen.
63
The anti-Lewis
Y
conjugate CMD-193 failed in
Phase 1, with unexpected and extended liver uptake.
64
Although the cause of
this unfortunate phenomenon is unknown, it should be noted that CMD-193 is
the only calicheamicin conjugate to be advanced with an IgG
1
antibody, the
rest having IgG
4
antibodies like gemtuzumab ozogamicin.
These initial failures reflect the diculty of targeting solid tumors, especially
in the Phase 1 setting of advanced disease. However, there has been renewed
interest in conjugates due to the on-going success of the tubulin-active may-
tansine conjugate of trastuzumab (T-DM1).
65
The antibody in this conjugate is
almost ideal, with restricted antigen expression, high antigen expression, and
rapid internalization. It is hoped that conjugates of different classes of cytotoxic
agents with antibodies to other such antigens will also find clinical success
against solid tumors.
References
1. B. Lowenberg and B. A. Downing, Jr., New Engl. J. Med., 1999, 341, 1051.
2. J. L. Shipley and J. N. Butera, Exp. Hematol., 2009, 37, 649.
3. G. Schiller, S. A. Feig, M. Territo, M. Wolin, M. Lill, T. Belin, L. Hunt,
S. Nime, R. Champlin and J. Gajewski, Br. J. Haematol., 1994, 88, 72.
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