Head-to-head comparison of DFO* and DFO chelators: selection of the best candidate for clinical Zr-immuno-PET.

Purpose: Almost all radiolabellings of antibodies with Zr currently employ the hexadentate chelator desferrioxamine (DFO). However, DFO can lead to unwanted uptake of Zr in bones due to instability of the resulting metal complex. DFO*-NCS and the squaramide ester of DFO, DFOSq, are novel analogues that gave more stable Zr complexes than DFO in pilot experiments.

Development of [11C]vemurafenib employing a carbon-11 carbonylative Stille coupling and preliminary evaluation in mice bearing melanoma tumor xenografts.

Over the last decade kinase inhibitors have witnessed tremendous growth as anti-cancer drugs. Unfortunately, despite their promising clinical successes, a large portion of patients does not benefit from these targeted therapeutics. Vemurafenib is a serine/threonine kinase inhibitor approved for the treatment of melanomas specifically expressing the BRAFV600E mutation.

Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines.

We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs.

A Novel Platinum(II)-Based Bifunctional ADC Linker Benchmarked Using 89Zr-Desferal and Auristatin F-Conjugated Trastuzumab.

Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs.

Development of novel ADCs: conjugation of tubulysin analogues to trastuzumab monitored by dual radiolabeling.

Tubulysins are highly toxic tubulin-targeting agents with a narrow therapeutic window that are interesting for application in antibody-drug conjugates (ADC). For full control over drug-antibody ratio (DAR) and the effect thereof on pharmacokinetics and tumor targeting, a dual-labeling approach was developed, wherein the drug, tubulysin variants, and the antibody, the anti-HER2 monoclonal antibody (mAb) trastuzumab, are radiolabeled. (131)I-radioiodination of two synthetic tubulysin A analogues, the less potent TUB-OH (IC50 > 100 nmol/L) and the potent TUB-OMOM (IC50, ~1 nmol/L), and their direct covalent conjugation to (89)Zr-trastuzumab were established.