• Alloantibodies are produced by the immune system in response to antigens it doesn’t recognize, such as those from a transplanted organ or a developing fetus.
• Alloimmunization can develop during pregnancy, when the mother’s immune system mistakenly identifies antigens from the fetus as a threat, and alloantibodies are formed.
• Alloantibodies are different from autoantibodies, which are antibodies that mistakenly attack a person’s own cells.
• Hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT) are two rare alloimmune conditions that are the result of an antigen mismatch between a mother and fetus.
• Johnson & Johnson is studying a potential therapy that may block maternal alloantibodies from targeting fetal red blood cells or platelets.
The human body has a powerful ability to repel invaders. When a foreign entity like a virus or bacteria enters, the immune system creates antibodies to destroy what it believes to be harmful antigens—which are molecular markers created by the pathogen.
But in rare cases, the immune system creates specific antibodies called alloantibodies. That happens when a foreign entity gets inside your body but isn’t a threat—for instance, a transplanted organ or a pregnancy.
When your immune system encounters human tissue containing antigens that are incompatible with your own, alloantibodies attack those antigens. Alloantibodies are different from autoantibodies, which are dysfunctional antibodies that mistakenly take aim at a person’s own healthy cells and tissues.
Alloantibodies are the reason that organ-transplant recipients are carefully screened to match their donor and then administered a cocktail of therapies for the rest of their lives to prevent organ rejection.
Alloantibodies in pregnancy, by contrast, crop up unexpectedly and can pose severe dangers, not to the mother, but to the fetus both before and after birth.
What causes alloantibodies in pregnancy?
“Every fetus is genetically 50 percent dad and 50 percent mom,” says May Lee Tjoa, Ph.D., Senior Director, Global Medical Affairs, Autoantibody and Maternal Fetal Immunology at Johnson & Johnson. In a typical pregnancy, explains Tjoa, “there’s a whole complex immune adaptation that prevents the mother’s body from rejecting the fetus.”
But this essential adaptation can be thrown off if the fetus contains cells with antigens (from the father’s DNA) that are incompatible with the mother’s cells.
When those fetal cells come into contact with the mother’s immune system, her body senses an antigen mismatch, deems them to be potentially harmful and creates alloantibodies. These alloantibodies can cross back through the placenta and begin to attack those cells in the fetus.
This alloantibody response can be dangerous to the health and life of the fetus or newborn.
What are the main alloimmune diseases in pregnancy?
Two similar yet distinct alloimmune diseases can develop during pregnancy:
1. Hemolytic disease of the fetus and newborn (HDFN)
• HDFN occurs when a mother’s immune system creates alloantibodies that target fetal red blood cells, which are critical to transporting oxygen throughout the developing baby’s body.
• “The risk with HDFN is fetal anemia, and in severe cases, fetal hydrops, which is a fluid buildup in the fetus that can result in a fetal death,” says Tjoa.
2. Fetal and neonatal alloimmune thrombocytopenia (FNAIT)
• FNAIT occurs when the maternal immune system produces alloantibodies that target fetal platelets, which are crucial for blood clotting.
• The result can be internal bleeding in the fetus if the alloantibodies damage the developing baby’s platelets. “The most severe outcome is a head bleed, or intracranial hemorrhage (ICH),” says Tjoa. This can lead to lifelong disability or death.
Both HDFN and FNAIT are categorized as rare diseases. HDFN is estimated to affect between 3 and 80 babies per 100,000 pregnancies, while FNAIT affects about 1 in 1,000.
Diagnosing and treating HDFN and FNAIT
The primary risk factor for having a fetus or newborn with HDFN or FNAIT is experiencing a previous pregnancy in which the baby was diagnosed with either disease.
HDFN can be mild in a first affected pregnancy, but later pregnancies can be more severe and must be monitored by ultrasound to potentially determine if the fetal anemia has developed and gauge whether an intervention is needed.
For HDFN, pregnant women are routinely given a blood test as part of prenatal care that can diagnose RhD incompatibility. (Rh is a protein found on the surface of red blood cells.)
If incompatibility is discovered, an injection of Rhogam is administered to the mother to prevent the formation of alloantibodies that can attack fetal red blood cells. But there are other antigens that can cause HDFN besides RhD antigens, and currently, it is not possible to prevent alloimmunization against these antigens.
If HDFN is detected in utero, the only current treatment is an intrauterine blood transfusion for the fetus—a complex and invasive technique that carries a risk of fetal death of 1 to 3%, according to studies. Sometimes treatment involves multiple intrauterine blood transfusions.
FNAIT, on the other hand, is usually not diagnosed until a baby is born with signs of thrombocytopenia (very low levels of platelets in the blood), including bruising, petechiae or more severe organ bleeds, including ICH.
In cases where a pregnancy is at risk for FNAIT (usually because the mother had a previous FNAIT pregnancy), the only available treatment is the off-label use of intravenous immunoglobulin (IVIG) during pregnancy. While IVIG may prevent or reduce the severity of FNAIT in a subsequent pregnancy, the U.S. Food and Drug Administration (FDA) has not determined if IVIG is safe or effective to treat FNAIT.
Developing therapies for pregnancy-related alloantibody diseases
One of the biggest challenges with treating any autoimmune or alloimmune disease is targeting the dysfunctional immune response without damaging the immune system as a whole.
Johnson & Johnson is currently investigating one targeted treatment for both HDFN and FNAIT that can potentially protect the fetus while also preserving overall immune function in both the mother and the fetus.
“We are investigating an antibody that blocks a receptor in the placenta that normally allows the transfer of antibodies from the maternal circulation to the fetal circulation,” says Tjoa. If approved, that antibody therapy may prevent maternal alloantibodies from entering the fetal blood system and destroying fetal red blood cells or platelets.
In 2024, the FDA granted fast-track designation for this potential therapy to reduce the risk of FNAIT in pregnant women. Later that year, the FDA also granted breakthrough designation for this therapy for the potential treatment of pregnant women at high risk of HDFN.
Both designations help expedite the development and review of a therapy by the FDA. Phase 3 clinical trials to evaluate the safety and efficacy of this treatment in FNAIT and HDFN are currently underway.
The ultimate goal would be for women at risk for HDFN or FNAIT to finally have access to an approved, relatively noninvasive therapy, “so that these babies may be born without any complications from HDFN or FNAIT,” Tjoa adds.
