VI Autologous Bone Marrow Transplantation.pdf - Blog Science ...

RADIOIMMUNOTHERAPY FOR BONE MARROW
TRANSPLANTATION PATIENTS
Huibert M. Vriesendorp,* Karel A. Dicke,** Syed M. Quadri*
* The University of Texas M.D. Anderson Cancer Center
Houston, Texas
** Houston Cancer Institute
Houston, Texas
GENERAL PERSPECTIVE
Radioimmunoglobulin therapy (RIT) is considered feasible and promising
since the late 1950's but remains an investigational new cancer treatment modality
till today. The relatively slow progress in RIT is caused by its complexity requiring
participation of many different scientific disciplines and allocation of
considerable resources. Continued interest in RIT appears justified for several
reasons. RIT is an active single agent in patients with relapsed Hodgkin's disease
or lymphoma.' 3
Bone marrow damage is the only side effect of RIT regularly
observed in human patients so far, which can be corrected by a bone marrow
transplant or hemopoietic growth factors u
~ 5
. The most important remaining
limitation to RIT is the relatively low uptake of radiolabeled antibody by tumor
tissues in human patients. Currently, the best RIT reagents deliver approximately
20 Gy to tumor in one week in human patients 6. Promising results have
been obtained in preclinical animal models, indicating the possibility of tumor
dose escalations in human patients by a factor 5 M
.
IMMUNOGLOBULIN PERMUTATIONS
Theoretical considerations indicate that radiolabeled monoclonal antibodies
deliver higher tumor doses than similarly labeled polyclonal antibodies. However,
non-specific binding of the murine monoclonal antibodies or immune
complexes to normal human liver prevents the realization of this principle in
vivo.3 Enzymatic removal of the CF fragment will decrease liver uptake. The resulting
F(ab')2 fragment will target the tumor, but rapidly split in two F(ab')
fragments. This fragment is quickly released by tumor and taken up by kidney
or excreted in urine 9
. F(ab')2 fragments are good diagnostic reagents, but have
tumor dwell times that are too short for the delivery of significant doses of radiation.
Removal of the Fc fragment decreases the immunogenicity of the
radioimmunoconjugate and increases the possibilities for repeated RIT cycles.
Stabilized F(ab')2 fragments, in which the labile interchain disulfide bridges are
replaced by more stable thioether linkages, appear to be more promising RIT
reagents in experimental animal models and need further analysis in human pa-
f j g j ^ g (9, and Quadri et al., submitted for publication)
Another method to circumvent the application of the full immunogenic, Fc
bearing mouse immunoglobulin is the use of "humanized" monoclonal antibod-
98 SIXTH INTERNATIONAL SYMPOSIUM ON AUTOLOGOUS BONE MARROW TRANSPLANTATION