Name:	Intravenous Immunoglobulin
Other Names:	Gammagard, IVIg
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Protein therapeutic; passive immunotherapy. IVIg is administered by intravenous infusion. It is believed that infusions have to be carried out at least once or twice a month in Alzheimer patients.
Mechanisms:	Natural anti-amyloid antibodies may reduce CNS and peripheral Aβ and improve cognition.
Development Status:	investigational in U.S.
FDA Phase:	Phase III
Primary Medical Role:	It was recently discovered that human immunoglobulins (Ig) contain antibodies that bind to β amyloid (Aβ) (reviewed in Weksler et al., 2005). IVIg may help to promote the clearance of Aβ from the brain, block Aβ toxicity in the brain, and improve cognitive function.
Role in Alzheimer's Disease:	Immunotherapy targeting β amyloid (Aβ) has been shown to arrest and partially reverse AD brain pathology in transgenic mouse models of AD. Data suggest that immunotherapy may have positive effects in some AD patients (Hock et al., 2003). Intravenous Immunoglobulin (IVIg) is obtained from the pooled plasma of healthy human blood donors, and contains natural anti-amyloid antibodies. In vitro data have demonstrated that human anti-Aβ antibodies inhibit fibril formation and neurotoxicity (Du et al., 2003). In the phase 1 safety and preliminary efficacy clinical trial (U.S.), eight Alzheimer patients were treated with IVIg (Gammagard S/D Immune Globulin Intravenous Human), donated by Baxter Healthcare Corporation. Seven patients completed the study and were evaluated by cognitive testing after 6 months of therapy. Cognitive function stopped declining in all seven patients and improved in six of the seven patients. In a phase 1 safety and preliminary efficacy clinical trial (Germany) five “clinically probable or possible” Alzheimer disease patients were treated with IVIg (Octagam®, donated by Octapharma [Langenfeld, Germany]) for 6 months. On the ADAS-cog a slight improvement was observed on neuropsychological testing at 6 months in all patients except one where the score did not change between baseline and at 6 months. A mean improvement of 3.7 ± 2.9 points was calculated. No patient deteriorated. A reduction in the CSF of total Aβ of 17.3–43.5 percent was also observed (Dodel et al., 2004).
Pharmacological Role:	Passive administration of anti-Aβ antibodies has been shown to attenuate amyloid plaque deposition and reduce cognitive deficits (DeMattos et al., 2001; Dodart et al., 2002).
Contraindications:	Exclusion Criteria: 1. Any other forms of dementia 2. Medical issues that might increase the risk of treatment with IGIV, 10%, such as: a. Significant problems with blood pressure, heart disease, clotting disorders, strokes or recent heart attacks b. Evidence of current bleeding in the brain by MRI c. Serious problems with the liver or kidneys d. Allergies to blood products 3. Medical issues that might interfere with the evaluation of the treatment of dementia or might make dementia worse, such as: a. Diabetes b. Recent treatment with chemotherapy or immune suppression c. The recent use of other investigational drugs, especially antibody therapy for AD d. Severe headaches or psychiatric problems 4. Prohibited Medications include: a. Taking immunosuppressive drugs b. Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) more than 3 times weekly (with the exception of aspirin daily), or currently receiving or has received any immunomodulating therapies within 3 months prior to screening c. Currently receiving or has received IGIV treatment within the 5 years prior to screening d. Currently receiving or has received any investigational biologic(s) (e.g. active immunization or passive immunotherapies with monoclonal or polyclonal antibodies) for AD at any time, or any investigational drug(s) for AD within 3 months prior to screening e. Current or recent (within 3 months prior to screening) participation in any other investigational drug or device studies
Side Effects:	IVIg therapy has been shown to be generally well tolerated, with patients experiencing only minor and infrequent side effects, such as chills following the infusion. Possible risks relating to use of IVIg include kidney failure, stroke, lung problems, heart failure, allergic reactions, and other problems. Because it is derived from human blood, IVIg carries with it a very small risk of communicable diseases such as hepatitis and HIV. However, in the United States there have been no documented cases of transmission of these diseases by IVIg over the past 10 years.
Evidence pro its efficacy:	IVIg is an antibody product derived from human plasma. IVIg has been used since 1979 for the treatment of immune disorders in children and adults, and has been safely used in hundreds of thousands of patients. IVIg is FDA-approved for the treatment of patients with primary immunodeficiencies, immune thrombocytopenic purpura (ITP), B cell chronic lymphocyctic leukemia (CLL), Kawasaki syndrome, and immunodeficiency associated with pediatric HIV and bone marrow transplantation. IVIg contained antibodies to several forms of β amyloid, including those thought to play a central role in the development of Alzheimer's. In a previous clinical trial to test efficacy of IVIg in Alzheimer disease, eight patients with mild to moderate Alzheimer disease, averaging 74 years of age, received one to four IVIg infusions per month at varying doses. Because the researchers wanted to track circulating levels of β amyloid and β amyloid antibodies, patients also underwent regular blood tests, as well as spinal taps to collect samples of spinal fluid. Patients were also given standard tests of memory and cognition to assess ongoing changes in mental function. Levels of anti-β amyloid antibodies and β amyloid increased significantly in blood after each IVIg infusion. This indicates that antibodies in IVIg altered the dynamics of β amyloid trafficking in the blood.
Companies:	Baxter Healthcare
Notes:	A Phase III study to determine whether IGIV treatment slows the rate or prevents the decline of dementia symptoms in individuals with mild-to-moderate Alzheimer's Disease was started in December 2008 and is actively recruiting participants. See Phase III trial details. The Phase II clinical trial is currently ongoing but no longer recruiting participants. See Phase II trial details. Interim data from this ongoing trial was reported at ICAD 2008. See ARF related news story. Updated: Feb 3, 2009.

References

Weksler ME, Gouras G, Relkin NR, Szabo P. The immune system, amyloid-beta peptide, and Alzheimer's disease. Immunol Rev. 2005 Jun 1;205:244-56. Abstract

Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Oct 1;75(10):1472-4. Abstract

Du Y, Wei X, Dodel R, Sommer N, Hampel H, Gao F, Ma Z, Zhao L, Oertel WH, Farlow M. Human anti-beta-amyloid antibodies block beta-amyloid fibril formation and prevent beta-amyloid-induced neurotoxicity. Brain. 2003 Sep 1;126 (Pt 9):1935-9. Abstract

Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003 Jul 8;61(1):46-54. Abstract

Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Müller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, De Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003 May 22;38(4):547-54. Abstract

Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002 May 1;5(5):452-7. Abstract

DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5. Abstract