An Efficient Conjugation Approach for Coupling Drugs to Native Antibodies via the Pt^IILinkerLxfor Improved Manufacturability of Antibody–Drug Conjugates

Abstract

The PtII linker [ethylenediamineplatinum(II)]2+, coined Lx, has emerged as a novel non‐conventional approach to antibody–drug conjugates (ADCs) and has shown its potential in preclinical in vitro and in vivo benchmark studies. A crucial improvement of the Lx conjugation reaction from initially <15 % to ca. 75–90 % conjugation efficiency is described, resulting from a systematic screening of all relevant reaction parameters. NaI, a strikingly simple inorganic salt additive, greatly improves the conjugation efficiency as well as the conjugation selectivity simply by exchanging the leaving chloride ligand on Cl‐Lx‐drug complexes (which are direct precursors for Lx‐ADCs) for iodide, thus generating I‐Lx‐drug complexes as more reactive species. Using this iodide effect, we developed a general and highly practical conjugation procedure that is scalable: our lead Lx‐ADC was produced on a 5 g scale with an outstanding conjugation efficiency of 89 %.

Metallodrugs in cancer nanomedicine

“…Although not common, some recent approaches have also exploited Pt(II) for structural roles e.g., as linkers to facilitate drug-antibody conjugation. 264 By contrast, Ru and its complexes have clearly not met the high expectations around them in the 2000s, where they were presented as one of the potential alternatives to Pt antineoplastics due, in part, to the lower side-effects offered by Ru compounds and the higher number of potential mechanisms of action. 75,77,103,265 In addition to the significantly lower share of research attention in Ru-as compared to Pt-nano-chemotherapeutics (2% versus 50%), the number of publications on nano-Rucompounds has plateaued in the last 10 years.…”

“…, as linkers to facilitate drug-antibody conjugation. 264 By contrast, Ru and its complexes have clearly not met the high expectations around them in the 2000s, where they were presented as one of the potential alternatives to Pt antineoplastics due, in part, to the lower side-effects offered by Ru compounds and the higher number of potential mechanisms of action. 75,77,103,265…”

Antibody–drug conjugates: Recent advances in linker chemistry

“…Furthermore, trastuzumab- Lx -MMAF at a dose of 15 mg/kg exhibited a better therapeutic effect than Kadcyla in a mouse xenograft tumor model. While the conjugation efficiency with this metal-organic linker to histidines was strongly improved recently 75 , the same linker can also be used for site-specific coupling to cysteines 76 .…”

The Chemistry Behind ADCs

“…A different conjugation strategy efficiently targeting histidine residues on native antibodies was recently reported by Merlul et al [ 102 ]. They introduced an original cationic organometallic Pt(II)-based linker, [ethylenediamineplatinum(II)] 2+ denoted Lx ( Figure 57 ).…”