The approximately 15-kDa variable domains of camelid heavy-chain-only antibodies (called Nanobodies) can easily be formatted as multivalent or multispecific single-chain proteins. Because fast excretion, however, they are less suitable for therapy cancer. In this study, we aimed improved tumor targeting a bivalent anti-epidermal growth factor receptor (EGFR) Nanobody (alphaEGFR-alphaEGFR) by fusion to unit binding albumin (alphaAlb). Biodistributions alphaEGFR-alphaEGFR,...

Given that overexpression of the epidermal growth factor receptor (EGFR) is found in many types human epithelial cancers, noninvasive molecular imaging this great interest. A number studies have employed monoclonal antibodies as probes; however, their characteristic long half-life bloodstream has encouraged development smaller probes. In study, an anti-EGFR nanobody-based probe was developed and tested comparison with cetuximab for application optical imaging. To aim, nanobody 7D12 were...

The human cytomegalovirus (HCMV), potentially associated with the development of malignancies, encodes constitutively active chemokine receptor US28. Previously, we have shown that US28 expression induces an oncogenic phenotype both in vitro and vivo. Microarray analysis revealed differential genes involved signaling US28-expressing NIH-3T3 cells. In particular, cyclooxygenase-2 (COX-2), a key mediator inflammatory diseases major determinant several forms cancer, was highly up-regulated....

The chemokine receptor CXCR7, belonging to the membrane-bound G protein-coupled superfamily, is expressed in several tumor types. Inhibition of CXCR7 with either small molecules or interference (si)RNA has shown promising therapeutic benefits models. With increased interest and effectiveness biologicals inhibiting receptors we made use "Nanobody platform" target CXCR7. Previously showed that Nanobodies, i.e. immunoglobulin single variable domains derived from naturally occurring heavy...

Hepatocyte growth factor (HGF) and its receptor c-Met are associated with increased aggressiveness of tumors poor prognostic outcome patients cancer. Here, we report the development characterization therapeutic anti-HGF (αHGF)-Nanobodies their potential for positron emission tomographic (PET) imaging to assess HGF expression in vivo. Two αHGF-Nanobodies designated 1E2 6E10 were identified, characterized, molecularly fused an albumin-binding Nanobody unit (Alb8) obtain serum half-life...

Antibody-PET imaging might be of value for the selection radioimmunotherapy (RIT) candidates to confirm tumor targeting and estimate radiation doses normal tissues. One requirements set such a scouting procedure is that biodistributions diagnostic therapeutic radioimmunoconjugates should similar. In present study we evaluated potential positron emitters zirconium-89 ((89)Zr) iodine-124 ((124)I) this approach, as these radionuclides have relatively long half-life matches with kinetics MAbs in...

The ∼15 kDa variable domains of camelid heavy-chain-only antibodies (called Nanobodies®) have the flexibility to be formatted as monovalent, monospecific, multivalent or multispecific single chain proteins with either fast slow pharmacokinetics. We report evaluation kinetic anti-epidermal growth factor receptor (EGFR) Nanobody 7D12, labelled (68)Ga via novel bifunctional chelate (BFC) p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS). Df-Bz-NCS has recently been introduced choice for (89)Zr...

The human monoclonal antibody (MAb) fragment L19-SIP is directed against extra domain B (ED-B) of fibronectin, a marker tumour angiogenesis. A clinical radioimmunotherapy (RIT) trial with 131I-L19-SIP was recently started. In the present study, after GMP production 124I and efficient 124I-L19-SIP, we aimed to demonstrate suitability 124I-L19-SIP immuno-PET for imaging angiogenesis at early-stage development as scouting procedure prior RIT. produced in compliant way via 124Te(p,n)124I...

Photoimmunodetection, in which monoclonal antibodies [mAbs] are labeled with fluorescent dyes, might have clinical potential for early detection and characterization of cancer. For this purpose, the dye should be coupled an inert way to mAb. In study, different equivalents IRDye800CW, a near-infrared dye, were 89Zr-labeled cetuximab bevacizumab, conjugates evaluated biodistribution studies. Radiolabeled mAbs used allow accurate quantification assessment number groups that can without...

Despite continuous improvement of treatment regimes, the mortality rates for non-small cell lung cancer (NSCLC) and head neck squamous carcinoma (HNSCC) remain disappointingly high novel anticancer agents are urgently awaited.We combined data from genome-wide siRNA screens on tumor lethality in a line.We identified 71 target genes that seem essential survival both types. We cluster 20 play an important role during G2-M phase transition, underlining importance this cell-cycle checkpoint...

Tubulysins are highly toxic tubulin-targeting agents with a narrow therapeutic window that interesting for application in antibody-drug conjugates (ADC). For full control over drug-antibody ratio (DAR) and the effect thereof on pharmacokinetics tumor targeting, dual-labeling approach was developed, wherein drug, tubulysin variants, antibody, anti-HER2 monoclonal antibody (mAb) trastuzumab, radiolabeled. (131)I-radioiodination of two synthetic A analogues, less potent TUB-OH (IC50 > 100...

Head and neck squamous cell carcinomas (HNSCCs) coincide with poor survival rates. The lack of driver oncogenes complicates the development targeted treatments for HNSCC. Here, we follow-up on two previous genome-wide RNA microRNA interference screens in HNSCC to cross-examine tumor-specific lethality by targeting ATM, ATR, CHEK1, or CHEK2. Our results uncover CHEK1 as most promising target expression is essential across a panel lines but redundant growth untransformed oral keratinocytes...

The application of intact monoclonal antibodies (mAbs) as targeting agents in nuclear imaging and radioimmunotherapy is hampered by the slow pharmacokinetics these molecules. Pretargeting with mAbs could be beneficial to reduce radiation burden patient, while using excellent capacity mAbs. In this study, we evaluated applicability Staudinger ligation pretargeting strategy an antibody-azide conjugate tumor-targeting molecule combination a small phosphine-containing imaging/therapeutic probe....

We describe a new method for biodistribution studies with IRDye800CW fluorescent antibody probes. This allows the quantification of tracer in percentage injected dose per gram tissue (% ID/g), and it is herein compared to generally used reference that makes use radioactivity.Cetuximab was conjugated both near-infrared fluorophore and/or positron emitter 89-zirconium, which nude mice bearing A431 human tumor xenografts. Positron emission tomography (PET) optical imaging were performed 24 h...

Tyrosine kinase inhibitors (TKIs) have experienced a tremendous boost in the last decade, where more than 15 small molecule TKIs been approved by FDA. Unfortunately, despite their promising clinical successes, large portion of patients remain unresponsive to these targeted drugs. For non-small cell lung cancer (NSCLC), effectiveness is dependent on mutational status epidermal growth factor receptor (EGFR). The exon 19 deletion as well L858R point mutation lead excellent sensitivity such...

Abstract The E48 antigen is a successfully explored molecular marker for the diagnosis and therapy of HNSCC. applicability as an HNSCC‐associated antigen, however, restricted due to its heterogeneous expression in 30% tumors; identification additional target antigens therefore desired. belongs Ly‐6 family, comprising group highly homologous, low m.w., GPI‐anchored surface proteins, which some show tissue‐restricted patterns. To identify novel human members with squamous cell‐associated...

RG7356 is a humanized antibody targeting the constant region of CD44. was radiolabeled with 89Zr for preclinical evaluations in tumor xenograft-bearing mice and normal cynomolgus monkeys to enable study its biodistribution role CD44 expression on uptake. Studies 89Zr-RG7356 were performed bearing xenografts that differ level (CD44+ or CD44-) responsiveness (resp non-resp): MDA-MB-231 (CD44+, resp), PL45 non-resp) HepG2 (CD44–, non-resp). Immuno-PET whole body studies determine organ uptake...

Lung cancer is the most common worldwide and on top of that has a very poor prognosis, which reflected by 5-year survival rate 5% to 15%. Radiotherapy an integral part treatment regimens for this type tumor, often combined with radiosensitizing cytotoxic drugs. In study, we identified many genes could potentially be exploited targeted radiosensitization using genome-wide siRNA screen in non-small cell lung (NSCLC) cells. The 433 siRNAs sensitize cells radiation. Validation experiments showed...