A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio

Sandstrï¿1⁄2m, K.

doi:10.3892/ijo.2012.1352

Cited by 12 publications

(16 citation statements)

References 22 publications

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“…5 However, even molecules larger than 70 kDa have been reported to accumulate in kidney to a limited extent. [6][7][8] Another factor that could influence these high BC values for the kidney is the distribution of the free label to the kidney. However, since we find increasing BC values with decreasing size of antibody fragments irrespective of the labeling, this effect may not contribute significantly.…”

Section: Discussionmentioning

confidence: 99%

Influence of molecular size on tissue distribution of antibody fragments

Krippendorff

Sharma

et al. 2015

mAbs

130

104

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Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues.

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Section: Discussionmentioning

confidence: 99%

Influence of molecular size on tissue distribution of antibody fragments

Krippendorff

Sharma

et al. 2015

mAbs

130

104

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“…Although intact mAbs are still most commonly used, they are not considered optimal for radio-immunodiagnostics. Their relatively large size (approximately 150 kDa) tends to cause unfavourable imaging kinetics due to slow plasma clearance, poor tumour penetration and higher risk of eliciting a host antibody response [10-12]. One solution to these obstacles has been to reduce the size of intact antibodies to smaller fragments, achieved either through enzymatic cleavage or by genetic engineering.…”

Section: Introductionmentioning

confidence: 99%

“…In a previous study, chimeric Fab and Fab 2 fragments of U36 radiolabelled with 125 I were characterized in vitro and in vivo and compared to the intact antibody. Tumour-to-blood ratios and tumour penetration were increased for Fab and Fab 2 compared with the intact antibody [12]. …”

Section: Introductionmentioning

confidence: 99%

In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study

et al. 2014

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BackgroundPatients with squamous cell carcinoma in the head and neck region (HNSCC) offer a diagnostic challenge due to difficulties to detect small tumours and metastases. Imaging methods available are not sufficient, and radio-immunodiagnostics could increase specificity and sensitivity of diagnostics. The objective of this study was to evaluate, for the first time, the in vivo properties of the radiolabelled CD44v6-targeting fragment AbD15179 and to assess its utility as a targeting agent for radio-immunodiagnostics of CD44v6-expressing tumours.MethodsThe fully human CD44v6-targeting Fab fragment AbD15179 was labelled with 111In or 125I, as models for radionuclides suitable for imaging with SPECT or PET. Species specificity, antigen specificity and internalization properties were first assessed in vitro. In vivo specificity and biodistribution were then evaluated in tumour-bearing mice using a dual-tumour and dual-isotope setup.ResultsBoth species-specific and antigen-specific binding of the conjugates were demonstrated in vitro, with no detectable internalization. The in vivo studies demonstrated specific tumour binding and favourable tumour targeting properties for both conjugates, albeit with higher tumour uptake, slower tumour dissociation, higher tumour-to-blood ratio and higher CD44v6 sensitivity for the 111In-labelled fragment. In contrast, the 125I-Fab demonstrated more favourable tumour-to-organ ratios for liver, spleen and kidneys.ConclusionsWe conclude that AbD15179 efficiently targets CD44v6-expressing squamous cell carcinoma xenografts, and particularly, the 111In-Fab displayed high and specific tumour uptake. CD44v6 emerges as a suitable target for radio-immunodiagnostics, and a fully human antibody fragment such as AbD15179 can enable further clinical imaging studies.

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“…The U36 antibody was labeled with 111 In using the chelator CHXA"-DTPA and the chimeric molecule showed promising results regarding bio-distribution and tumor uptake in HNSCC bearing nude mice (Sandstrom et al 2008). F(ab′)2 and Fab′ fragments of U36 were even superior to the mAb regarding bio-distribution and accumulation in the tumor (Sandstrom et al 2012). Although the tumor uptake of 125 I-F(ab′) 2 was lower as compared to the 125 I-labeled mAb U36, a higher tumorto-blood ratio was observed.…”

Section: Monoclonal Antibodies Against Cd44v6 In Head and Neck Cancermentioning

confidence: 98%

Perspectives of CD44 targeting therapies

Orian-Rousseau

Ponta

2014

Arch Toxicol

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CD44 is a family of single-span transmembrane glycoproteins. Members of this family differ in the extracellular domain where ten variant exons are either excluded or included in various combinations. CD44 isoforms participate in many physiological processes including hematopoiesis, regeneration, lymphocyte homing and inflammation. Most importantly, they are involved in pathological processes and in particular in cancer. In several types of tumors, CD44 together with other antigens specifies for cancer stem cell populations. Mechanistically, CD44 proteins act as receptors for hyaluronan, co-receptor for receptor tyrosine kinases (RTKs) or G-protein-coupled receptors or provide a platform for metalloproteinases. For all these reasons, targeting CD44 may be a successful approach in cancer therapy. In this review, we discuss the various possibilities of targeting CD44. Among these are the production of CD44 ectodomains, antibodies, peptides or aptamers. Also inhibition of CD44 expression has been proposed. Finally, the function of CD44 as a hyaluronan receptor was also taken advantage of. We are convinced that the success of these therapies will depend on an increased understanding of the molecular functions of specific CD44 isoforms in particular in cancer stem cells.

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A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio

Cited by 12 publications

References 22 publications

Influence of molecular size on tissue distribution of antibody fragments

Influence of molecular size on tissue distribution of antibody fragments

In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study

Perspectives of CD44 targeting therapies

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