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Experimental Therapeutics, Preclinical Pharmacology |
The Restoration of Appearance and Function Trust Institute of Plastic Surgery, Mount Vernon Hospital [N. K., S. H., J. O., J. K.], and Cancer Research Trust, Gray Laboratory [G. W.], Northwood, Middlesex HA6 2RN and HA6 2JR, respectively, United Kingdom
Monoclonal antibodies (MAbs) against high-molecular-weight
melanoma-associated antigen (HMW-MAA) have been used in
vivo to target melanoma. More recently, single chain Fv (scFv)
antibody fragments against HMW-MAA have been described that may improve
melanoma targeting. However, there have been few in vivo
studies with anti-melanoma scFvs because these have proved difficult to
label with isotopes (e.g., 99mTc) suitable
for imaging. We have generated a series of scFvs against HMW-MAA by
chain shuffling and antibody phage selection on melanoma cells. In
preliminary experiments we identified one scFv (RAFT3) as suitable for
in vivo melanoma targeting. Direct radiolabeling of
RAFT3 scFv with 99mTc was simple, yielding a
radiochemical purity of >90%. The label remained stable for 24 h
in vitro. 125I- and
99mTc-labeled RAFT3 scFv were tested in a nude mouse
xenograft model for human melanoma and were compared with the parent
MAb LHM2 and its F(ab')2 fragment versus
nonmelanoma-specific MAb and scFv. RAFT3 scFv accumulated specifically
in the tumor and showed greater tumor specificity compared with LHM2
with faster pharmacokinetics (t1/2
,
8 min; t1/2ß, 189 min; and
t1/2, 37 min; t1/2ß, 384 min,
respectively) and reduced background in liver, lung, and spleen.
Nonspecific accumulation of 99mTc-labeled RAFT3 scFv in the
kidney was high but tumor:normal tissue ratios were better compared
with 125I-labeled RAFT3 scFv and LHM2 F(ab')2.
Overall, tumor-targeting efficiency at equivalent time points was
scFv > IgG > F(ab')2 in good agreement with
previously described scFvs engineered for 99mTc labeling.
We discuss the potential use of RAFT3 scFv for imaging and therapy of
metastatic melanoma.
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