Exposure to Monoclonal Antibodies

Excluding those classified as orphan drugs, there are 10 monoclonal antibodies currently used to treat cancer, asthma, or rheumatoid arthritis. Five are composed of various types of humanized immunoglobulin G (IgG) and two of murine IgG. The approved indications include leukemia, metastatic carcinoma of the colon or rectum, squamous cell carcinoma of the head and neck, non-Hodgkin's lymphoma, metastatic breast cancer, and moderate to severe chronic diseases such as asthma and rheumatoid arthritis.

The antineoplastic agents are alemtuzumab (Campath), bevacizumab (Avastin), cetuximab (Erbitux), gemtuzumab ozogamicin (Mylotarg), ibritumomab tiuxetan (Zevalin), panitumumab (Vectibix), tositumomab and iodine 131 (Bexxar), and trastuzumab (Herceptin). The ninth member of this group, rituximab (Rituxan), is also used as an antirheumatic agent.

Exposure of the embryo and fetus should be expected whenever these antibodies are used in pregnancy. Although their molecular weights are very high, two are known to cross the placenta: Rituxan in humans and Herceptin in monkeys. The transplacental passage of the other antibodies has not been studied, but endogenous IgG crosses the placenta. Moreover, the long elimination half-lives ranging from about 2 to 19 days will place these antibodies at the maternal-fetal interface for prolonged periods. Animal reproduction studies have not been conducted with Bexxar, Campath, Erbitux, or Zevalin. Studies in pregnant animals with Herceptin and Rituxan suggested low risk for humans, whereas the suggested risk was higher for Avastin, Mylotarg, and Vectibix.

Bexxar, Campath, Erbitux, Mylotarg, Zevalin, and Rituxan may cause severe, infusion-related toxicity, including hypotension. Although premedication is used to lessen this effect, this toxicity could have deleterious effects on placental perfusion, resulting in harm to the embryo and fetus.

Human pregnancy data are available only for Herceptin and Rituxan. For Herceptin, the human pregnancy experience is limited to five cases, two of which involved first-trimester exposure. Although no congenital malformations were observed, fetal renal toxicity, as evidenced by oligohydramnios or anhydramnios, was observed in three cases. The toxicity might have been caused by inhibition of human epidermal growth factor receptor 2 (HER-2) in the fetal kidneys. The renal toxicity was reversible, and all five infants developed normally. However, there is potential for other toxicity because HER-2 protein expression is high in many embryonic tissues, such as cardiac and neural tissues.

Six pregnancies have been exposed to Rituxan, including two in the first trimester. No structural anomalies were noted, and all infants appeared to be healthy at birth. One had depletion of B lymphocytes, but B-cell counts returned to normal at about 4 months of age. No increase in infectious disease was noted in any of the infants.

Reports of exposure to Bexxar and Mylotarg during pregnancy are unlikely. Bexxar, indicated for non-Hodgkin's lymphoma, contains radioactive iodine and is contraindicated in pregnancy. Mylotarg, a combination of gemtuzumab (IgG4k) conjugated with the cytotoxic antitumor antibiotic calicheamicin, is indicated for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older. Mylotarg caused significant developmental toxicity at a small fraction of the human dose in the only experimental animal species tested. The therapeutic regimen for Zevalin, another agent for non-Hodgkin's lymphoma, should preclude its use in pregnancy because it includes two radioactive components as well as Rituxan, and the risk to the embryo and fetus appears to be high.

Omalizumab (Xolair), a monoclonal antibody used for moderate to severe persistent asthma, selectively binds to human IgE and has a half-life of 26 days. It has not been studied in animals or humans, but probably crosses the placenta. Reproduction studies in monkeys suggest that the risk in human pregnancy is low, but the human pregnancy experience is limited. In clinical trials, 29 women became pregnant during treatment with Xolair, which was stopped when pregnancy was diagnosed. Among these patients, there were 4 spontaneous abortions (SABs), 3 elective abortions, 11 normal deliveries, and 11 ongoing pregnancies. The number of SABs, all occurring in the first trimester, is within the expected incidence for recognized pregnancies.

A full assessment of the risk of monoclonal antibodies during pregnancy is not possible because of the very limited or absent human pregnancy data, including a lack of long-term evaluation of exposed offspring. Nevertheless, these agents are used for life-threatening diseases and, if indicated, should not be withheld from a pregnant woman—with the exception of Bexxar, Mylotarg, and possibly Zevalin.

Excluding those classified as orphan drugs, there are 10 monoclonal antibodies currently used to treat cancer, asthma, or rheumatoid arthritis. Five are composed of various types of humanized immunoglobulin G (IgG) and two of murine IgG. The approved indications include leukemia, metastatic carcinoma of the colon or rectum, squamous cell carcinoma of the head and neck, non-Hodgkin's lymphoma, metastatic breast cancer, and moderate to severe chronic diseases such as asthma and rheumatoid arthritis.

The antineoplastic agents are alemtuzumab (Campath), bevacizumab (Avastin), cetuximab (Erbitux), gemtuzumab ozogamicin (Mylotarg), ibritumomab tiuxetan (Zevalin), panitumumab (Vectibix), tositumomab and iodine 131 (Bexxar), and trastuzumab (Herceptin). The ninth member of this group, rituximab (Rituxan), is also used as an antirheumatic agent.

Exposure of the embryo and fetus should be expected whenever these antibodies are used in pregnancy. Although their molecular weights are very high, two are known to cross the placenta: Rituxan in humans and Herceptin in monkeys. The transplacental passage of the other antibodies has not been studied, but endogenous IgG crosses the placenta. Moreover, the long elimination half-lives ranging from about 2 to 19 days will place these antibodies at the maternal-fetal interface for prolonged periods. Animal reproduction studies have not been conducted with Bexxar, Campath, Erbitux, or Zevalin. Studies in pregnant animals with Herceptin and Rituxan suggested low risk for humans, whereas the suggested risk was higher for Avastin, Mylotarg, and Vectibix.

Bexxar, Campath, Erbitux, Mylotarg, Zevalin, and Rituxan may cause severe, infusion-related toxicity, including hypotension. Although premedication is used to lessen this effect, this toxicity could have deleterious effects on placental perfusion, resulting in harm to the embryo and fetus.

Human pregnancy data are available only for Herceptin and Rituxan. For Herceptin, the human pregnancy experience is limited to five cases, two of which involved first-trimester exposure. Although no congenital malformations were observed, fetal renal toxicity, as evidenced by oligohydramnios or anhydramnios, was observed in three cases. The toxicity might have been caused by inhibition of human epidermal growth factor receptor 2 (HER-2) in the fetal kidneys. The renal toxicity was reversible, and all five infants developed normally. However, there is potential for other toxicity because HER-2 protein expression is high in many embryonic tissues, such as cardiac and neural tissues.

Six pregnancies have been exposed to Rituxan, including two in the first trimester. No structural anomalies were noted, and all infants appeared to be healthy at birth. One had depletion of B lymphocytes, but B-cell counts returned to normal at about 4 months of age. No increase in infectious disease was noted in any of the infants.

Reports of exposure to Bexxar and Mylotarg during pregnancy are unlikely. Bexxar, indicated for non-Hodgkin's lymphoma, contains radioactive iodine and is contraindicated in pregnancy. Mylotarg, a combination of gemtuzumab (IgG4k) conjugated with the cytotoxic antitumor antibiotic calicheamicin, is indicated for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older. Mylotarg caused significant developmental toxicity at a small fraction of the human dose in the only experimental animal species tested. The therapeutic regimen for Zevalin, another agent for non-Hodgkin's lymphoma, should preclude its use in pregnancy because it includes two radioactive components as well as Rituxan, and the risk to the embryo and fetus appears to be high.

Omalizumab (Xolair), a monoclonal antibody used for moderate to severe persistent asthma, selectively binds to human IgE and has a half-life of 26 days. It has not been studied in animals or humans, but probably crosses the placenta. Reproduction studies in monkeys suggest that the risk in human pregnancy is low, but the human pregnancy experience is limited. In clinical trials, 29 women became pregnant during treatment with Xolair, which was stopped when pregnancy was diagnosed. Among these patients, there were 4 spontaneous abortions (SABs), 3 elective abortions, 11 normal deliveries, and 11 ongoing pregnancies. The number of SABs, all occurring in the first trimester, is within the expected incidence for recognized pregnancies.

A full assessment of the risk of monoclonal antibodies during pregnancy is not possible because of the very limited or absent human pregnancy data, including a lack of long-term evaluation of exposed offspring. Nevertheless, these agents are used for life-threatening diseases and, if indicated, should not be withheld from a pregnant woman—with the exception of Bexxar, Mylotarg, and possibly Zevalin.

Excluding those classified as orphan drugs, there are 10 monoclonal antibodies currently used to treat cancer, asthma, or rheumatoid arthritis. Five are composed of various types of humanized immunoglobulin G (IgG) and two of murine IgG. The approved indications include leukemia, metastatic carcinoma of the colon or rectum, squamous cell carcinoma of the head and neck, non-Hodgkin's lymphoma, metastatic breast cancer, and moderate to severe chronic diseases such as asthma and rheumatoid arthritis.

The antineoplastic agents are alemtuzumab (Campath), bevacizumab (Avastin), cetuximab (Erbitux), gemtuzumab ozogamicin (Mylotarg), ibritumomab tiuxetan (Zevalin), panitumumab (Vectibix), tositumomab and iodine 131 (Bexxar), and trastuzumab (Herceptin). The ninth member of this group, rituximab (Rituxan), is also used as an antirheumatic agent.

Exposure of the embryo and fetus should be expected whenever these antibodies are used in pregnancy. Although their molecular weights are very high, two are known to cross the placenta: Rituxan in humans and Herceptin in monkeys. The transplacental passage of the other antibodies has not been studied, but endogenous IgG crosses the placenta. Moreover, the long elimination half-lives ranging from about 2 to 19 days will place these antibodies at the maternal-fetal interface for prolonged periods. Animal reproduction studies have not been conducted with Bexxar, Campath, Erbitux, or Zevalin. Studies in pregnant animals with Herceptin and Rituxan suggested low risk for humans, whereas the suggested risk was higher for Avastin, Mylotarg, and Vectibix.

Bexxar, Campath, Erbitux, Mylotarg, Zevalin, and Rituxan may cause severe, infusion-related toxicity, including hypotension. Although premedication is used to lessen this effect, this toxicity could have deleterious effects on placental perfusion, resulting in harm to the embryo and fetus.

Human pregnancy data are available only for Herceptin and Rituxan. For Herceptin, the human pregnancy experience is limited to five cases, two of which involved first-trimester exposure. Although no congenital malformations were observed, fetal renal toxicity, as evidenced by oligohydramnios or anhydramnios, was observed in three cases. The toxicity might have been caused by inhibition of human epidermal growth factor receptor 2 (HER-2) in the fetal kidneys. The renal toxicity was reversible, and all five infants developed normally. However, there is potential for other toxicity because HER-2 protein expression is high in many embryonic tissues, such as cardiac and neural tissues.

Six pregnancies have been exposed to Rituxan, including two in the first trimester. No structural anomalies were noted, and all infants appeared to be healthy at birth. One had depletion of B lymphocytes, but B-cell counts returned to normal at about 4 months of age. No increase in infectious disease was noted in any of the infants.

Reports of exposure to Bexxar and Mylotarg during pregnancy are unlikely. Bexxar, indicated for non-Hodgkin's lymphoma, contains radioactive iodine and is contraindicated in pregnancy. Mylotarg, a combination of gemtuzumab (IgG4k) conjugated with the cytotoxic antitumor antibiotic calicheamicin, is indicated for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older. Mylotarg caused significant developmental toxicity at a small fraction of the human dose in the only experimental animal species tested. The therapeutic regimen for Zevalin, another agent for non-Hodgkin's lymphoma, should preclude its use in pregnancy because it includes two radioactive components as well as Rituxan, and the risk to the embryo and fetus appears to be high.

Omalizumab (Xolair), a monoclonal antibody used for moderate to severe persistent asthma, selectively binds to human IgE and has a half-life of 26 days. It has not been studied in animals or humans, but probably crosses the placenta. Reproduction studies in monkeys suggest that the risk in human pregnancy is low, but the human pregnancy experience is limited. In clinical trials, 29 women became pregnant during treatment with Xolair, which was stopped when pregnancy was diagnosed. Among these patients, there were 4 spontaneous abortions (SABs), 3 elective abortions, 11 normal deliveries, and 11 ongoing pregnancies. The number of SABs, all occurring in the first trimester, is within the expected incidence for recognized pregnancies.

A full assessment of the risk of monoclonal antibodies during pregnancy is not possible because of the very limited or absent human pregnancy data, including a lack of long-term evaluation of exposed offspring. Nevertheless, these agents are used for life-threatening diseases and, if indicated, should not be withheld from a pregnant woman—with the exception of Bexxar, Mylotarg, and possibly Zevalin.