Drug Targeting Organ-Specific Strategies

224 8 Strategies for Specific Drug Targeting to Tumour Cells
moural concentration of doxorubicin at a level required to achieve regression. It is likely
therefore that immunoconjugates of doxorubicin will be only effective in minimal-disease
settings.
In general, trials with radioimmunoconjugates reported higher response rates in patients
with haematological malignancies when compared with patients with solid tumours. The
most impressive studies with non-myeloablative regimens reported objective responses in
70–80% of patients with chemotherapy-refractory B-cell lymphomas, a median response duration
of 12 months and minimal toxicity using 131-I-labelled anti-CD20 [134]. In trials with
myeloablative regimens, performed in conjunction with autologous haematopoeitic bone
marrow or stem cell transplantation, responses have been seen in 95% of patients, complete
responses in 85%, with a progression-free survival of 62% and overall survival of 93% with a
median follow-up of 2 years [135,136].The estimated 4-year overall and progression-free survival
rates were reported to be 68 and 42%, respectively [137].
Anti-CD45 antibody BC8 labelled with 131-I may reduce the rate of tumour relapse and
has acceptable toxicity in patients with AML,ALL or myelodysplastic syndrome who underwent
stem-cell rescue [138]. Of 25 patients treated with advanced AML and myelodysplastic
syndrome, seven were disease-free at 15–89 months post-transplantation. Of nine patients
with advanced ALL, three were disease-free at 23, 58 and 70 months post-transplantation, respectively.
As with the monoclonal antibody therapies described above, B-cell malignancies would be
the most attractive targets for anti-CD3 bispecific monoclonal antibody-based immunotherapy
[139]. Several phase I/II clinical trials have been described using BsMAb for non B-cell
malignancies. BIS-1, a BsMAb directed against the TAA EGP-2 and the CD3/T-cell receptor
complex on T lymphocytes was studied in renal [140] and lung cancer [141]. In carcinoma patients
with EGP-2 positive malignant ascites or pleural exudates, local administration of exvivo
IL-2-activated autologous lymphocytes and BIS-1, resulted in both anti-tumour effects
and a strong local inflammatory reaction [141]. In patients with advanced breast or ovarian
cancer administration of BsMAb directed against FcγRI or FcγRIII and HER-2/neu resulted
in elevated plasma levels of cytokines [142,143].
The biological effects observed at tumour sites indicate that BsMAbs effectively penetrate
tissue. However, trials are limited by the toxicity caused by induction of a ‘cytokine storm’ or
by the complex pharmacokinetics. Furthermore, T-cell directed BsMAb approaches are hindered
by difficulties in mobilizing and activating T and NK effector cells. Recent attention,
therefore, has focused on BsMAbs which target myeloid effectors [79].
8.6.2 Pro-drugs
ADEPT strategies have been described but only the carboxypeptidase G2 approach has
been tested in patients so far. In a phase I clinical trial, patients with non-resectable metastatic
or locally recurrent colorectal carcinoma were treated with ADEPT. Carboxypeptidase
G2 activity was found in metastatic tumour biopsies.The pro-drug was converted into the active
drug but leakage into the bloodstream also occurred [22,144].
Clinical trials with ‘monotherapy’ pro-drug strategies are in progress, but have not yet
been evaluated.