Prophylactic administration of HPA-1a–specific antibodies prevents fetal/neonatal alloimmune thrombocytopenia in mice

• Published in: Blood 2022-11, Vol.140 (20), p.2146-2153
• Main Authors: Zhi, Huiying, Sheridan, Douglas, Newman, Debra K., Newman, Peter J.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Human Platelet; Female; Fetus; Humans; Integrin beta3; Isoantibodies; Mice; Pregnancy; Prenatal Care; Thrombocytopenia, Neonatal Alloimmune - prevention & control
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022015666

•A novel alloantigen-specific model has been developed and used to examine the efficacy of a prophylactic treatment regimen for FNAIT.•The resulting preclinical data provide guidance for the use of HPA-1a–specific antibodies to prevent FNAIT in humans. [Display omitted] Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal alloantibodies directed against paternally inherited human platelet alloantigens (HPAs) present on the surface of fetal and neonatal platelets. There are currently no approved therapies for the prevention of FNAIT. We report herein the ability of 2 human HPA-1a–specific therapeutic candidates, one a polyclonal, and the other a monoclonal antibody, to prevent alloimmunization in a novel preclinical mouse model of FNAIT. Both antibody preparations effected the rapid and complete elimination of HPA-1a+ platelets from circulation and prevented the development of HPA-1a alloantibodies. HPA-1a− female mice treated prophylactically with anti–HPA-1a antibody prior to exposure to HPA-1a+ platelets gave birth to HPA-1a+/− pups with significantly improved platelet counts and no bleeding symptoms. These preclinical data establish both the potential and threshold exposure targets for prophylactic treatment with HPA-1a–specific antibodies for the prevention of FNAIT in humans. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare but potentially life-threatening condition in pregnancy that can lead to intracranial bleeding in the fetus or neonate. Zhi et al describe that prophylactic administration of a human polyclonal or monoclonal antihuman platelet antigen (HPA)-1a in a preclinical and alloantigen-specific mouse model of FNAIT can rapidly clear HPA-1a–positive platelets from the circulation, thereby preventing alloimmunization and the onset of FNAIT. This finding provides the rationale for this preventative approach to be tested in clinical trials.