Biodistributions of intact monoclonal antibodies and fragments of BLCA-38, a new prostate cancer directed antibody

Carter, Teresa; Sterling-Levis, Katy; Ow, Kim; Doughty, Larissa; Hattarki, Meghan; Shapira, Deborah; Hewish, Dean R.; Kortt, Alexander A.; Russell, Pamela J.

doi:10.1007/s00262-003-0460-1

Cited by 16 publications

(8 citation statements)

References 18 publications

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“…A major class of therapeutic proteins consists of chimeric or human monoclonal antibodies 3–6. While there are several published reports that show a typical biodistribution profile of a human or chimeric 125 I‐IgG,11, 19, 27, 31, 32 a typical pattern of T/S ratios observed for IgG mAbs has not been systematically established. Since IgGs are relatively large in size (MW of ∼150 kDa), they cannot easily pass through biomembrane and distribute primarily into vascular space and extracellular fluids, with expected T/S ratios of less than one 1, 3–5…”

Section: Resultsmentioning

confidence: 99%

Biodistribution of [125I]-labeled therapeutic proteins: Application in protein drug development beyond oncology**All authors are current or former employees of Wyeth, Inc.

Vugmeyster¹,

DeFranco²,

Szklut³

et al. 2010

Journal of Pharmaceutical Sciences

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Section: Resultsmentioning

confidence: 99%

Biodistribution of [125I]-labeled therapeutic proteins: Application in protein drug development beyond oncology**All authors are current or former employees of Wyeth, Inc.

Vugmeyster¹,

DeFranco²,

Szklut³

et al. 2010

Journal of Pharmaceutical Sciences

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“…In this work, uptake in LNCaP-PSCA tumors with the radioiodinated 2B3 minibody reached 9.3 (± 2.3) %ID/g at 21 h and the tumor-to-blood ratio was nearly 3. Thus, in the same xenograft model, the 2B3 minibody reached a comparable tumor uptake level with an improved tumor-to-blood ratio at 21 h, instead of 144 h. Protease derived 125 I-J591 F(ab’) 2 (110 kDa) and Fab (50 kDa) fragments were also evaluated for their ability to improve target-to-background ratios in LNCaP xenografts (37). The tumor and blood activity for 125 I-J591 F(ab’) 2 was 5.17 and 4.41 %ID/g, respectively, at 24 h. The tumor uptake with the 125 I-J591 Fab reached a modest 1.85 %ID/g at 24 h but importantly a tumor-to-blood ratio of 3.44 was achieved (37).…”

Section: Discussionmentioning

confidence: 97%

Humanized Radioiodinated Minibody For Imaging of Prostate Stem Cell Antigen–Expressing Tumors

Leyton

Olafsen

Lepin

et al. 2008

Clinical Cancer Research

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Purpose: Prostate stem cell antigen (PSCA) is a cell surface glycoprotein that is overexpressed in prostate cancer, including hormone refractory disease. Previous preclinical studies showed the intact anti-PSCA antibodies, 1G8 and hu1G8, localized specifically to PSCA-expressing xenografts. Optimal micro positron emission tomography (microPET) imaging using hu1G8, however, required a delay of 168 hours postinjection. In this study, the 2B3 minibody (an 80-kDa engineered antibody fragment) has been produced for rapid targeting and imaging. Experimental Design: A gene encoding a PSCA-specific minibody,V L -linker-V H -hinge-huIgG1 C H 3, was assembled. The minibody was expressed by secretion from mammalian cells and purified by cation exchange chromatography. Relative affinity and specificity were determined by competition ELISA and flow cytometry. Serial microPET imaging using a 124 I-labeled minibody was conducted at 4 and 21 hours in mice bearing LAPC-9 AD, LAPC-9 AI, PC-3, and LNCaP-PSCA human prostate cancer xenografts. Tumor and tissue biodistribution was determined, and region of interest analysis of the images was conducted. Results: Yields of 20 mg/L purified 2B3 minibody were obtained that showed specific binding to LNCaP-PSCA cells. Purified 2B3 minibody showed specific binding to LNCaP-PSCA cells with an apparent affinity of 46 nmol/L. Radioiodinated 2B3 minibody showed rapid nontarget tissue and blood clearance kinetics (t 1/2 h = 11.2 hours). MicroPET scanning using the 124

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“…The antibodies targeting PSMA, Mindin/RG-1 and PSCA have all required days (2-7 days) for the blood to clear enough in order to obtain high contrast tumor images. For PSMA, improvements that produced good tumor-to-blood ratios at early time points were achieved by enzymatically reducing the molecular weight of PSMA-targeting antibodies (Carter et al, 2004). Radioiodinated Fab and F(ab') 2 fragments displayed optimal targeting times at 24 and 48 h, respectively.…”

Section: Introductionmentioning

confidence: 99%

Engineered humanized diabodies for microPET imaging of prostate stem cell antigen-expressing tumors

Leyton

Olafsen

Sherman

et al. 2008

Protein Engineering Design and Selection

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We have previously demonstrated preclinical in vivo targeting of prostate stem cell antigen (PSCA) using a humanized anti-PSCA 2B3 monoclonal antibody (mAb). However, humanization resulted in 5-fold loss of apparent affinity relative to the parental mAb (1 nM). In this study, diabodies (scFv dimers of 55 kDa) were generated from 2B3 including variants with different linker lengths as well as back-mutations to original murine residues to improve affinity. Parental 2B3 (p2B3) and back-mutated 2B3 (bm2B3) diabodies (Dbs) with five-or eight-amino acid linkers (p2B3-Db5, p2B3-Db8, bm2B3-Db5 and bm2B3-Db8) were evaluated for binding to PSCA by flow cytometry and affinities were determined by surface plasmon resonance. Back-mutation restored the affinity from 5.4 to 1.9 nM. Stability, evaluated by size exclusion, revealed that diabodies with eight-residue linkers existed as a mixture of dimeric and monomeric species at low concentrations (1 mg/ml). Shortening the linker from eight to five residues improved dimer stability, notably in the bm2B3-Db8 compared with bm2B3-Db5. Both p2B3-Db8 and bm2B3-Db8 were radioiodinated with 124 I and evaluated by serial micro-positron emission tomography imaging in mice bearing LAPC-9 human prostate cancer xenografts. Localization in LAPC-9 xenografts was seen at 4 h, whereas at 20 h most of the activity had cleared from the tumor. Highest tumor-to-background contrast ratios and best images were obtained at 12 h. Although the higher affinity bm2B3-Db8 demonstrated improved tumor retention at later time points (20 h), it did not improve tumor targeting or imaging compared with p2B3-Db8 at 12 h.

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Biodistributions of intact monoclonal antibodies and fragments of BLCA-38, a new prostate cancer directed antibody

Abstract: BLCA-38 can target prostate cancer in vivo almost as effectively as J591. Given that J591 is used clinically, BLCA-38, which targets a different antigen, has potential for radioimmunoscintigraphy and for therapeutic targeting of prostate cancer.

Cited by 16 publications

References 18 publications

Biodistribution of [125I]-labeled therapeutic proteins: Application in protein drug development beyond oncology**All authors are current or former employees of Wyeth, Inc.

Biodistribution of [125I]-labeled therapeutic proteins: Application in protein drug development beyond oncology**All authors are current or former employees of Wyeth, Inc.

Humanized Radioiodinated Minibody For Imaging of Prostate Stem Cell Antigen–Expressing Tumors

Engineered humanized diabodies for microPET imaging of prostate stem cell antigen-expressing tumors

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