Pre-existing antitherapeutic antibodies against the Fc region of the hu14.18K322A mAb are associated with outcome in patients with relapsed neuroblastoma

J Immunother Cancer. 2020 Mar;8(1):e000590. doi: 10.1136/jitc-2020-000590.

Abstract

Purpose: Patients with cancer receiving tumor-reactive humanized monoclonal antibody (mAb) therapy can develop a human antihuman antibody (HAHA) response against the therapeutic mAb. We evaluated for HAHA in patients with neuroblastoma treated in a phase I study of humanized anti-GD2 mAb (immunoglobulin (Ig)G1 isotype), hu14.18K322A (NCT00743496). The pretreatment sera (collected prior to mAb treatment) from 9 of 38 patients contained antitherapeutic antibodies, even though they had no prior mAb exposure. We sought to characterize these pre-existing antitherapeutic antibodies (PATA).

Experimental design: The PATA+ pretreatment samples were characterized via ELISA; clinical associations with PATA status were evaluated.

Results: Pretreatment sera from eight of nine PATA+ patients also bound rituximab and demonstrated preferential ELISA reactivity against the Fc portions of hu14.18K322A and rituximab as compared with the Fab portions of these mAbs. These PATA+ sera also recognized dinutuximab (human IgG1 isotype) and mouse IgG2a isotype mAbs, but not a mouse IgG1 isotype or the fully human panitumumab (IgG2 isotype) mAb. Of the 38 treated patients, only 4 patients (all in the PATA+ cohort) demonstrated no disease progression for >2.5 years without receiving further therapy (p=0.002).

Conclusions: This study demonstrates an association between clinical outcome and the presence of PATA against determinant(s) on the Fc component of the therapeutic mAb, suggesting that the PATA may be playing a role in augmenting mAb-based antitumor effects. Further analyses for the presence of PATA in a larger cohort of patients with relapsed neuroblastoma, analyses of their clinical correlates, identification of their immunological targets, and potential antitumor mechanisms are warranted.

Keywords: anti-GD2; hu14.18K322A; human antihuman antibody (HAHA); immunotherapy; mAb; neuroblastoma; pre-existing antibodies; pre-existing antitherapeutic antibodies (PATA); rituximab.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Female
  • Humans
  • Mice
  • Neoplasm Recurrence, Local
  • Neuroblastoma
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Hu14.18K322A monoclonal antibody

Associated data

  • ClinicalTrials.gov/NCT00743496