Enhancing IgG distribution to lung mucosal tissue improves protective effect of anti–Pseudomonas aeruginosa antibodies
M. Jack Borrok, Antonio DiGiandomenico, Nurten Beyaz, Gabriela M. Marchetti, Arnita S. Barnes, Kristen J. Lekstrom, Sandrina S. Phipps, Michael P. McCarthy, Herren Wu, William F. Dall’Acqua, Ping Tsui, Ruchi Gupta
M. Jack Borrok, Antonio DiGiandomenico, Nurten Beyaz, Gabriela M. Marchetti, Arnita S. Barnes, Kristen J. Lekstrom, Sandrina S. Phipps, Michael P. McCarthy, Herren Wu, William F. Dall’Acqua, Ping Tsui, Ruchi Gupta
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Research Article Infectious disease Therapeutics

Enhancing IgG distribution to lung mucosal tissue improves protective effect of anti–Pseudomonas aeruginosa antibodies

Abstract

IgG antibodies are abundantly present in the vasculature but to a much lesser extent in mucosal tissues. This contrasts with antibodies of the IgA and IgM isotype that are present at high concentration in mucosal secretions due to active delivery by the polymeric Ig receptor (pIgR). IgG is the preferred isotype for therapeutic mAb development due to its long serum half-life and robust Fc-mediated effector function, and it is utilized to treat a diverse array of diseases with antigen targets located in the vasculature, serosa, and mucosa. As therapeutic IgG antibodies targeting the luminal side of mucosal tissue lack an active transport delivery mechanism, we sought to generate IgG antibodies that could be transported via pIgR, similarly to dimeric IgA and pentameric IgM. We show that an anti–Pseudomonas aeruginosa IgG fused with pIgR-binding peptides gained the ability to transcytose and be secreted via pIgR. Consistent with these results, pIgR-binding IgG antibodies exhibit enhanced localization to the bronchoalveolar space when compared with the parental IgG antibody. Furthermore, pIgR-binding mAbs maintained Fc-mediated functional activity and promoted enhanced survival compared with the parental mAb in a P. aeruginosa acute pneumonia model. Our results suggest that increasing IgG accumulation at mucosal surfaces by pIgR-mediated active transport can improve the efficacy of therapeutic mAbs that act at these sites.

Authors

M. Jack Borrok, Antonio DiGiandomenico, Nurten Beyaz, Gabriela M. Marchetti, Arnita S. Barnes, Kristen J. Lekstrom, Sandrina S. Phipps, Michael P. McCarthy, Herren Wu, William F. Dall’Acqua, Ping Tsui, Ruchi Gupta

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Figure 4

pIgR-binding Cam-003 fusions elicit opsonophagocytic killing and improved protection against lethal challenge in a P. aeruginosa acute pneumonia model.

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pIgR-binding Cam-003 fusions elicit opsonophagocytic killing and improve...
(A) Opsonophagocytosis assay with luminescent P. aeruginosa serogroup 05 strain PAO1 (PAO1.lux). OPK with Cam-003–QRN, Cam-003–KLKL, and Cam-003 are shown with the isotype control IgG R347. (B–D) Survival of BALB/c mice prophylactically immunized with an IgG isotype control R347, Cam-003, and either Cam-003–QRN (B) or Cam-003–KLKL (C and D) prior to i.n. infection with P. aeruginosa strain 6077. Results are represented as Kaplan-Meier survival curves; differences in survival were calculated by the log-rank test (Mantel-Cox). Data are representative of at least 2 independent experiments; n = 10 per group for survival experiments. (B) Cam-003 and Cam-003–QRN had significantly better protection than the isotype control at both doses tested (P < 0.0001 for both 5 and 10 mg/kg doses; 4.5 × 105 CFU inculcation). Cam-003–QRN survival was significantly improved compared with Cam-003, as well (P = 0.0014 for 5 mg/kg doses and P = 0.0098 for 10 mg/kg doses). (C) At 5 × 105 CFU, Both Cam-003 and Cam-003–KLKL were protective compared with R347 at both doses (P = 0.017, 2 mg/kg Cam-003; P = 0.0004, 6 mg/kg Cam-003; P < 0.0001, 2 and 6 mg/kg doses of Cam-003–KLKL). Cam-003–KLKL survival was superior to Cam-003 when comparing both the 2 mg/kg doses (P = 0.0042) and 6 mg/kg doses (P = 0.017). (D) At an 8 × 105 CFU inoculum dose, Cam-003 and Cam-003–KLKL survival was again enhanced compared with R347 (P < 0.0001, 2 mg/kg Cam-003; P = 0.0002, 6 mg/kg Cam-003; P < 0.0001, Cam-003–KLKL), with Cam-003–KLKL survival also enhanced compared with Cam-003 (P = 0.017, 6 mg/kg; not significant, 2 mg/kg).