Biomedical subjects

J Odili

Publications and source records attributed to J Odili.

4 recordsLinked to original sources

PubMed2002

Reducing renal accumulation of single-chain Fv against melanoma-associated proteoglycan by coadministration of L-lysine.

In view of the rising melanoma incidence and the absence of effective treatments for metastatic disease, there is an urgent need for new methods that allow the early detection of melanoma. To this end, in vivo detection by patient imaging with single-chain Fv (scFv) antibody fragments is an attractive diagnostic approach. However, high non-specific accumulation of scFvs in the kidney reduces image quality in this body area and prevents the use of scFvs for melanoma radioimmunotherapy. We have tested the effect of coadministration of L-lysine with (125)I-labelled scFvs against melanoma-associated proteoglycan on kidney accumulation in a nude mouse xenograft model. Coadministration of L-lysine had no significant effect on tumour accumulation of scFvs or blood clearance, but decreased kidney accumulation by factors of 2.25, 2.3, 6.3 and 5.8, respectively, at 1, 3, 6 and 18 h post-injection, and improved tumour to muscle contrast. The reduction in kidney accumulation was maximal at time points that can be extrapolated to patient studies. The time dependence of the effect suggests that further improvements could be achieved with an optimized dosing regimen. When combined with other strategies to reduce kidney accumulation of scFvs, coadministration of L-lysine has the potential to significantly improve tumour to kidney contrast.

Animals↗

PubMed2001

Improved production by domain inversion of single-chain Fv antibody fragment against high molecular weight proteoglycan for the radioimmunotargeting of melanoma.

Melanoma is among the few cancers with rising incidence. Currently there is no effective treatment for metastatic disease, but improved detection of melanoma has the potential to benefit the management of patients with early disease. Radioimmunodection by imaging with single-chain Fv (scFv) antibody fragments is one such emerging diagnostic method. However, the amount of scFv that can be produced at a scale suitable for use in patients is limiting. We have previously shown that the bacterial expression of a scFv derived from a monoclonal antibody (MAb) specific for melanoma-associated proteoglycan can be increased by light chain shuffling. In this report we show that a further increase in expression yield can be obtained by reversing the usual V(H)-V(L) orientation of scFvs to V(L)-V(H). Such seemingly minor changes have previously been reported to have unexpected effects on the in vitro and in vivo binding properties of recombinant antibodies. Our results show that reversal of the V domain orientation of the scFv improves expression by 150% without an adverse effect on melanoma binding in vitro and tumor targeting in vivo. Therefore, our results show that alteration of V domain orientation can improve the production yield of clinically useful antibody fragments. When used in combination with other antibody engineering approaches for increased antibody production changing the domain orientation is a simple strategy to achieve significant improvements in the production of scFvs for tumor radioimmunodetection for patient studies.

Antibodies, Neoplasm↗

PubMed2000

Are triglyceride breast implants really biocompatible?

A case of augmentation mammaplasty with triglyceride implants is presented. Histological examination of the capsules 3 years postimplantation showed retained, irregular, refractile yellow-brown fragments embedded in granulomatous tissue.

Adult↗

PubMed2000

In vivo targeting of malignant melanoma by 125Iodine- and 99mTechnetium-labeled single-chain Fv fragments against high molecular weight melanoma-associated antigen.

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 antimelanoma 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 (t(1/2)alpha, 8 min; t(1/2)beta, 189 min; and t(1/2)alpha, 37 min; t(1/2)beta, 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.

Animals↗