Novel antibody–antibiotic conjugate eliminates intracellular S. aureus

Lehar, Sophie M.; Pillow, Thomas H.; Xu, Min; Staben, Leanna; Kajihara, Kimberly K.; Vandlen, Richard; DePalatis, Laura; Raab, Helga; Hazenbos, Wouter L. W.; Morisaki, J. Hiroshi; Kim, Janice; Park, Summer; Darwish, Martine; Lee, Byoung-Chul; Hernandez, Hilda; Loyet, Kelly M.; Lupardus, P.J.; Fong, Rina; Yan, Donghong; Chalouni, Cécile; Luis, Elizabeth; Khalfin, Yana; Plise, Emile G.; Cheong, Jonathan; Lyssikatos, Joseph P.; Strandh, Magnus; Koefoed, Klaus; Andersen, Peter S.; Flygare, John A.; Tan, Man Wah; Brown, Eric J.; Mariathasan, Sanjeev

doi:10.1038/nature16057

Cited by 682 publications

(760 citation statements)

References 44 publications

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“…These points were resolved in the studies described here, as evidenced from the drug stability characteristics, and the high potencies and specificities of the ADCs containing quaternary ammonium linkers. Recently, in parallel with our ADC efforts, a val-cit-dipeptide-based quaternary ammonium linker was reported for the conjugation of a rifalogue antibiotic for an antibody-antibiotic conjugate (AAC) approach to treat intracellular methicillin-resistant S. aureus (28). Taken together, these results underscore the applicability of this approach for targeted drug delivery.…”

Section: Discussionmentioning

confidence: 58%

Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates

Burke

Hamilton

Pires

et al. 2016

Molecular Cancer Therapeutics

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A quaternary ammonium-based drug-linker has been developed to expand the scope of antibody-drug conjugate (ADC) payloads to include tertiary amines, a functional group commonly present in biologically active compounds. The linker strategy was exemplified with a b-glucuronidase-cleavable auristatin E construct. The drug-linker was found to efficiently release free auristatin E (AE) in the presence of b-glucuronidase and provide ADCs that were highly stable in plasma. Anti-CD30 conjugates comprised of the glucuronide-AE linker were potent and immunologically specific in vitro and in vivo, displaying pharmacologic properties comparable with a carbamate-linked glucuronide-monomethylauristatin E control. The quaternary ammonium linker was then applied to a tubulysin antimitotic drug that contained an N-terminal tertiary amine that was important for activity. A glucuronide-tubulysin quaternary ammonium linker was synthesized and evaluated as an ADC payload, in which the resulting conjugates were found to be potent and immunologically specific in vitro, and displayed a high level of activity in a Hodgkin lymphoma xenograft. Furthermore, the results were superior to those obtained with a related tubulysin derivative containing a secondary amine N-terminus for conjugation using previously known linker technology. The quaternary ammonium linker represents a significant advance in linker technology, enabling stable conjugation of payloads with tertiary amine residues.Mol Cancer Ther; 15(5); 938-45. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 58%

Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates

Burke

Hamilton

Pires

et al. 2016

Molecular Cancer Therapeutics

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“…These findings can help guide the design of future ADCs for maximal efficacy and optimal therapeutic window. Beyond ADCs, our results may also be instructive for the development of emerging therapeutics that are dependent on cleavage technologies, such as antibody-antibiotics conjugates (37,38). Understanding how protease-cleavable linkers operate can help better design and anticipate challenges for these types of therapies.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin B Is Dispensable for Cellular Processing of Cathepsin B-Cleavable Antibody–Drug Conjugates

Caculitan¹,

Chuh²,

Ma³

et al. 2017

Cancer Research

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107

102

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Antibody-drug conjugates (ADC) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline [VC(S)] linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload. Mass spectrometry studies of payload release suggested that other cysteine cathepsins can cleave the VC(S) linker. Also, ADCs with a nonprotease-cleavable enantiomer, the VC(R) isomer, mediated effective cell killing with a cysteine-VC(R)-MMAE catabolite generated by lysosomal catabolism. Based on these observations, we altered the payload to a pyrrolo[2,1-c][1,4]benzodiazepine dimer (PBD) conjugate that requires linker cleavage in order to bind its DNA target. Unlike the VC-MMAE ADCs, the VC(S)-PBD ADC is at least 20-fold more cytotoxic than the VC(R)-PBD ADC. Our findings reveal that the VC(S) linker has multiple paths to produce active catabolites and that antibody and intracellular targets are more critical to ADC efficacy. These results suggest that protease-cleavable linkers are unlikely to increase the therapeutic index of ADCs and that resistance based on linker processing is improbable.

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“…proposed a novel therapeutic using antibody-antibiotic conjugates to clear intracellular reservoirs of Staphylococcus aureus. 24 Similar strategies could also be used to eliminate persistent maternal GBS colonization and to potentially reduce the risk of neonatal infection. A previous study reported that serotype Ib GBS treated with sub-inhibitory concentrations of b-lactam antibiotics, including penicillin, increased killing of GBS by phagocytes.…”

Section: Cps Type Percent Survivalmentioning

confidence: 99%

Differing mechanisms of surviving phagosomal stress among group BStreptococcusstrains of varying genotypes

et al. 2016

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Group B Streptococcus (GBS), a leading cause of neonatal sepsis and meningitis, asymptomatically colonizes up to 30% of women and can persistently colonize even after antibiotic treatment. Previous studies have shown that GBS resides inside macrophages, but the mechanism by which it survives remains unknown. Here, we examined the ability of 4 GBS strains to survive inside macrophages and then focused on 2 strains belonging to sequence type (ST)-17 and ST-12, to examine persistence in the presence of antibiotics. A multiple stress medium was also developed using several stressors found in the phagosome to assess the ability of 30 GBS strains to withstand phagosomal stress. The ST-17 strain was more readily phagocytosed and survived intracellularly longer than the ST-12 strain, but the ST-12 strain was tolerant to ampicillin unlike the ST-17 strain. Exposure to sub-inhibitory concentrations of ampicillin and erythromycin increased the level of phagocytosis of the ST-17 strain, but had no effect on the ST-12 strain. In addition, blocking acidification of the phagosome decreased the survival of the ST-17 strain indicating a pHdependent survival mechanism for the ST-17 strain. Congruent with the macrophage experiments, the ST-17 strain had a higher survival rate in the multiple stress medium than the ST-12 strain, and overall, serotype III isolates survived significantly better than other serotypes. These results indicate that diverse GBS strains may use differing mechanisms to persist and that serotype III strains are better able to survive specific stressors inside the phagosome relative to other serotypes.

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Novel antibody–antibiotic conjugate eliminates intracellular S. aureus

Cited by 682 publications

References 44 publications

Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates

Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates

Cathepsin B Is Dispensable for Cellular Processing of Cathepsin B-Cleavable Antibody–Drug Conjugates

Differing mechanisms of surviving phagosomal stress among group BStreptococcusstrains of varying genotypes

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