Phase 1 study of MEDI3902, an investigational anti–Pseudomonas aeruginosa PcrV and Psl bispecific human monoclonal antibody, in healthy adults

Ali, Omar; Yu, Xiang-Qing; Robbie, Gabriel J.; Wu, Yuling; Shoemaker, Kathryn; Yu, Li; DiGiandomenico, Antonio; Keller, Ashley; Anude, Chuka J.; Hernandez‐Illas, Martha; Bellamy, Terramika; Falloon, Judith; Dubovsky, Filip; Jafri, Hasan S.

doi:10.1016/j.cmi.2018.08.004

Cited by 84 publications

(65 citation statements)

References 18 publications

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“…Specific-pathogen-free (SPF) mice were treated with a single dose of antibacterial MAb on day 0 or with a human-equivalent dose of broad-spectrum antibiotics for 5 days. A single dose of MAb was given because the half-life of human IgG in mice is 7 to 10 days, and MAbs such as MEDI4893 and MEDI3902 are administered as a single dose in human clinical trials (29,30). Fecal samples were collected on days 0, 7, and 14 from mice treated with a clinical candidate MAb targeting Staphylococcus aureus (MEDI4893*) or humanequivalent doses of antibiotics used to treat S. aureus infections (vancomycin [VAN], levofloxacin [LVX], and linezolid [LZD]).…”

Section: Resultsmentioning

confidence: 99%

Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function

Jones-Nelson

Tovchigrechko

Glover

et al. 2020

Antimicrob Agents Chemother

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Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.

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Section: Resultsmentioning

confidence: 99%

Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function

Jones-Nelson

Tovchigrechko

Glover

et al. 2020

Antimicrob Agents Chemother

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“…Another product from AstraZeneca PLC (formerly MedImmune) is MEDI3902, which is a bi-specific antibody targeting both the T3SS (PcrV), the same target as the KaloBios product, but in addition, also targets a surface polysaccharide (Psl) [55], which is essential for biofilm formation and virulence of P. aeruginosa [56,57]. MEDI3902 was successful in a Phase I trial [58] and was evaluated for HAP/VAP infections caused by P. aeruginosa in a Phase II trial. Like the other Hu-mAb from AstraZeneca PLC, this product was also dosed i.v., excluded patients on antibiotics, and only patients positive for P. aeruginosa were enrolled.…”

Section: Previous Failures Lead To Current Successmentioning

confidence: 99%

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

Zurawski

McLendon

2020

Antibiotics

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In the beginning of the 21st century, the frequency of antimicrobial resistance (AMR) has reached an apex, where even 4th and 5th generation antibiotics are becoming useless in clinical settings. In turn, patients are suffering from once-curable infections, with increases in morbidity and mortality. The root cause of many of these infections are the ESKAPEE pathogens (Enterococcus species, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli), which thrive in the nosocomial environment and are the bacterial species that have seen the largest rise in the acquisition of antibiotic resistance genes. While traditional small-molecule development still dominates the antibacterial landscape for solutions to AMR, some researchers are now turning to biological approaches as potential game changers. Monoclonal antibodies (mAbs)—more specifically, human monoclonal antibodies (Hu-mAbs)—have been highly pursued in the anti-cancer, autoimmune, and antiviral fields with many success stories, but antibody development for bacterial infection is still just scratching the surface. The untapped potential for Hu-mAbs to be used as a prophylactic or therapeutic treatment for bacterial infection is exciting, as these biologics do not have the same toxicity hurdles of small molecules, could have less resistance as they often target virulence proteins rather than proteins required for survival, and are narrow spectrum (targeting just one pathogenic species), therefore avoiding the disruption of the microbiome. This mini-review will highlight the current antibacterial mAbs approved for patient use, the success stories for mAb development, and new Hu-mAb products in the antibacterial pipeline.

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“…Phenotypic antibody screening, using an ELISA-based whole bacterial binding assay, was successfully used to discover a therapeutic mAb against the Pseudomonas aeruginosa exopolysaccharide Psl, a target which would have been missed using target-based screening methods 35 . A 1 7 bispecific antibody MEDI3902, targeting Psl and PcrV (inhibiting type III secretion), recently completed phase 1 clinical trials 36,37 .…”

Section: Binding Phenotypes Correlate With Differences In Serum Resismentioning

confidence: 99%

A novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes of Escherichia coli ST131

Maes

Dyson

Smith

et al. 2020

Preprint

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The increase of antimicrobial resistance (AMR), and lack of new classes of licensed antimicrobials, have made alternative treatment options for AMR pathogens increasingly attractive. Recent studies have demonstrated anti-bacterial efficacy of a humanised monoclonal antibody (mAb) targeting the O25b O-antigen of Escherichia coli ST131. To evaluate the phenotypic effects of antibody binding to diverse clinical E. coli ST131 O25b bacterial isolates in high-throughput, we designed a novel mAb screening method using highcontent imaging (HCI) and image-based morphological profiling to screen a mAb targeting the O25b O-antigen. Screening the antibody against a panel of 86 clinical E. coli ST131 O25:H4 isolates revealed 4 binding phenotypes: no binding (18.60%), weak binding (4.65%), strong binding (69.77%) and strong agglutinating binding (6.98%). Impaired antibody binding could be explained by the presence of insertion sequences or mutations in O-antigen or lipopolysaccharide core biosynthesis genes, affecting the amount, structure or chain length of the O-antigen. The agglutinating binding phenotype was linked with lower O-antigen density, enhanced antibody-mediated phagocytosis and increased serum susceptibly. This study highlights the need to screen candidate mAbs against large panels of clinically relevant isolates, and that HCI can be used to evaluate mAb binding affinity and potential functional efficacy against AMR bacteria.

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Phase 1 study of MEDI3902, an investigational anti–Pseudomonas aeruginosa PcrV and Psl bispecific human monoclonal antibody, in healthy adults

Abstract: Phase 1 study results of MEDI3902 in healthy subjects support further evaluation of its safety and efficacy in subjects at risk for P. aeruginosa pneumonia.

Cited by 84 publications

References 18 publications

Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function

Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

A novel therapeutic antibody screening method using bacterial high-content imaging reveals functional antibody binding phenotypes of Escherichia coli ST131

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