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New Chemically-Activated Antigen Could Expedite Development Of HIV Vaccine
September 26th, 2009
Scientists working to develop a vaccine for the human immunodeficiency virus (HIV) report they have created the first antigen that induces protective antibodies capable of blocking infection of human cells by genetically-diverse strains of HIV. The new antigen differs from previously-tested vaccines by virtue of its chemically-activated property that enables close sharing of electrons and produces strong covalent bonding. Researchers used a mouse model to generate the antibodies. The report by researchers at The University of Texas Health Science Center at Houston is online and will appear in a print issue of the Journal of Biological Chemistry in November.
“The complexity of HIV has for long thwarted development of an effective HIV vaccine. Our findings open a new path toward an effective preventative and therapeutic vaccine,” said Sudhir Paul, Ph.D., the study’s senior author and a professor in the Department of Pathology and Laboratory Medicine at The University of Texas Medical School at Houston. “The new antigen is a prototype vaccine. This prototype successfully eliminates nature’s restrictions on the production of broadly-neutralizing antibodies to HIV by the immune system.”
Thirty-three million people were living with HIV at the end of 2007, according to the World Health Organization. That same year, nearly 3 million people became newly infected, and 2 million died of acquired immunodeficiency syndrome or AIDS, which occurs at the most advanced stages of HIV infection. Vaccines work by introducing an antigen into the body, which spurs the immune system to produce antibodies that guard against infection. Previously-tested HIV vaccine candidates stimulated vigorous production of antibodies to the mutable segments of the virus envelope. But, these vaccine candidates did not stimulate the production of antibodies to the regions essential for virus attachment to host T cells, the process that initiates infection.
Scientists in Paul’s laboratory used a chemically-activated form of the HIV envelope protein gp120 to stimulate the production of mouse monoclonal antibodies that block infection of cultured human cells by genetically-diverse HIV strains from around the world. Paul said these same antibodies can be found in humans who remain free of AIDS despite long-term HIV infection. “HIV infection itself stimulates production of this class of antibodies, but the amount is too small to control infection. The challenge is to boost production of the protective antibodies in humans using a vaccine.”
Because of the genetic variability of HIV, most antibodies fail to stop infection initiated by thousands of different HIV strains responsible for the pandemic. “Dr. Paul’s team has developed a revolutionary antibody technology and used it to overcome major obstacles to a vaccine for HIV. They identified antibodies that neutralized 100 percent of strains drawn from the major viral subtypes. Furthermore, they have developed ways to immunize animals to produce them. No previous vaccine candidate has even approached these objectives,” said Robert L. Hunter, M.D., Ph.D., professor and chairman of the Department of Pathology and Laboratory Medicine at the UT Medical School at Houston.
The vaccine prototype builds on Paul’s earlier discovery that a tiny stretch of amino acids numbered 421-433 in gp120 can serve as the Achilles heel of HIV. “Unlike the changeable regions of its envelope, this region must remain constant to attach to T cells. Equally important, HIV can survive only if the body’s immune system fails to produce antibodies to this region. The virus minimizes production of antibodies to the vulnerable region because it also silences B lymphocytes, the cells responsible for producing antibodies,” Paul said. “In nature, microbial antigens stimulate antibody synthesis when they bind antibodies on the surface of B cells by weak noncovalent forces. In the case of HIV, noncovalent binding of its cell attachment site induces a state of B cell tolerance, permitting infection to proceed unchecked. Our covalent vaccination approach breaks the tolerance and stimulates production of antibodies that inactivate the virus.”
The tolerance signal is converted to a stimulatory signal because strong covalent binding to the B cells liberates a large amount of energy that is not available in traditional binding reactions, Paul said. Moreover, the prototype vaccine contains two modular antigenic regions. Binding of one region generates a stimulatory signal that overcomes the tolerance signal.
“There is another advantage. B cells have the unique capability of producing antibodies adapted to recognize the chemical groups we placed in the prototype vaccine. The adaptations impart enzyme-like activity to the antibodies, which results in exceptionally stable HIV binding, and sometimes, in catalytic breakdown of the viral coat. Consequently, the antibodies inactivate HIV effectively,” Paul said.
“The failure of previous HIV vaccine trials has produced pessimism about the prospect of effective HIV vaccination. Our approach is promising but additional studies are necessary. To expedite development of the vaccine, we must maximize the antibody response and focus it even more at the HIV cellular attachment site,” said Yasuhiro Nishiyama, Ph.D., lead author and an associate professor at UT Medical School.
“While the prototype vaccine induces antibodies that neutralize infection of isolated human cells, we must also show that the antibodies prevent the natural process of infection within the body,” said Stephanie Planque, Ph.D., co-author and researcher in Paul’s laboratory.
“The induction of antibodies that neutralize infection of human blood cells by diverse strains of HIV from various parts of the world is an important milestone. This is an entirely new vaccination approach that might bypass the natural constraints on developing effective immunity against HIV,” said Carl Hanson, Ph.D., study co-author and head of the Retrovir us Diagnostic Section of the Viral and Rickettsial Disease Laboratory of the California Department of Public Health.
Others contributors in the study from the Department of Pathology and Laboratory Medicine at the UT Medical School, were: Yukie Mitsuda, Ph.D.; Giovanni Nitti; Hiroaki Taguchi, Ph.D.; Lei Jin, Ph.D.; Jindrich Symersky, Ph.D.; Stephane Boivin, Ph.D.; and Marcin Sienczyk, Ph.D. Maria Salas of the Viral and Rickettsial Disease Laboratory also contributed to the study.
The journal article is titled “Towards Effective HIV Vaccination: Induction of Binary Epitope Reactive Antibodies with Broad HIV Neutralizing Activity.” The research was funded by the National Institutes of Health and the Texas Higher Education Coordinating Board.
Source:
Robert Cahill
University of Texas Health Science Center at Houston
Sangamo BioSciences Announces Plans To Initiate A Second Clinical Trial Of CCR5-ZFP Therapeutic To Treat HIV/AIDS
September 26th, 2009
Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced that the US Food and Drug Administration (FDA) has reviewed and accepted an Investigational New Drug (IND) application to initiate an open-label, repeat-dosing Phase 1 clinical trial (SB-728-T-902) of the company’s ZFN-based therapeutic, SB-728-T. A single dose Phase 1 clinical study of SB-728-T was initiated in February 2009 and is ongoing at the University of Pennsylvania. Both Phase 1 studies are designed primarily to evaluate the safety and tolerability of this ZFP Therapeutic(TM) approach, however subjects’ CD4 T-cell counts, levels of CCR5-modified T-cells and viral burden will also be monitored.
“Opening a second Phase 1 clinical trial of this exciting new approach to HIV/AIDS treatment enables us to expedite clinical and commercial development of SB-728-T. We are very pleased with the FDA’s decision enabling us to expand this program and move forward quickly with a repeat-dosing trial,” said Dale Ando, M.D., Sangamo’s chief medical officer and vice president of therapeutic development.
“The best approach to controlling HIV is by preventing infection of cells in the first place. Since 1996, when CCR5 was validated as a target for HIV therapy, the goal has been to recapitulate the naturally-occurring protection against viral infection exhibited by individuals who have the CCR5-delta32 mutation. We have the ability to disrupt the CCR5 gene and make human T-cells resistant to infection by CCR5-specific strains of HIV. In this trial we will be evaluating SB-728-T in subjects that have well-controlled levels of virus but have sub-optimal recovery of CD-4+ T-cell counts despite long-term triple drug therapy. This group represents approximately thirty percent of all HIV-infected patients in the US and may particularly benefit from this novel T-cell ZFP Therapeutic approach.”
Based on Sangamo’s zinc finger DNA-binding protein nuclease (ZFN) technology, SB-728-T has been shown in an animal model of HIV infection to lead to an increase in CD4+ T-cell counts, a reduction in viral load and expansion of CCR5-modified T-cells, suggesting resistance to HIV.
“Although it is still early days, we are encouraged by what we have seen in pre-clinical experiments and in the ongoing Phase 1 clinical trial that is being run by collaborators at the University of Pennsylvania,” commented Edward Lanphier, Sangamo’s president and CEO. “This new study is another important step in our mission to establish ZFP Therapeutics as a major new therapeutic product development platform. Moving our first ZFN technology-based product efficiently through the development process is vital to that goal. SB-728-T represents a new treatment paradigm for the treatment of HIV and we are very excited to expand its clinical development.”
CCR5 is a co-receptor that enables HIV to enter and infect cells of the immune system. It has been observed that individuals carrying a natural mutation of their CCR5 gene, CCR5-delta32, are highly resistant to infection by HIV, despite high-risk behaviors. These individuals, lacking a functional CCR5 (approximately 1-2% of the general population), are otherwise immunologically “normal”. A variety of small molecule and antibody antagonists of CCR5 binding have been tested and developed as potential therapeutic agents for the treatment of HIV infection. In addition, there is a recent report of a patient who had both HIV infection and leukemia and received a bone marrow transplant from a donor carrying the CCR5 mutation. After the successful bone marrow transplant, HIV treatment was discontinued and the virus could not be found in the circulating blood several months after the procedure. Sangamo’s ZFNs are designed to modify the DNA sequence encoding CCR5. This modification can occur directly in T-cells with only a brief exposure to the ZFNs. Once the modification is made to the T-cell’s CCR5 gene it is permanently disrupted.
About the SB-728-T Clinical Trial (SB-728-T-902)
The study is an open-label Phase 1 clinical trial to evaluate the safety and tolerability of repeat infusions of autologous (a patient’s own) CD4+ T cells genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). The trial will enroll a total of nine HIV infected subjects on long-term, stable anti-retroviral therapy whose virus is undetectable in their blood by conventional methods but who have exhibited suboptimal CD4+ T-cell gains. The trial will have three dosing cohorts. The first cohort to be treated will receive a single dose, the second cohort, two doses at fourteen day intervals and the third cohort, three doses at fourteen day intervals. The subjects in each cohort will be treated sequentially and monitored for 2 months after their last treatment before an additional subject is treated. After this period of evaluation and monitoring has passed successfully, the next cohort will be treated, again sequentially. Subjects will remain on their existing antiviral therapy while receiving treatment with SB-728-T. The primary objective of the study is to evaluate the safety and tolerability of SB-728-T. In addition to safety monitoring, data will be collected on the expansion and persistence of ZFN-modified cells, CD4+ cell counts and viral load.
Preclinical Data
Preclinical data on SB-728-T were published in the journal Nature Biotechnology (Perez E. E. et al., Nat Biotechnol. 2008 Jul; 26(7):808-16.) and presented at the joint meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Diseases Society of America (IDSA) in Washington, DC in October 2008. The results demonstrate that a one-time exposure to CCR5-specific ZFNs resulted in the generation of an HIV-resistant population of human primary T-cells by the permanent genetic modification of the CCR5 gene. These ZFN-modified CD4 T-cells expanded stably in HIV-infected cultures for several weeks and behaved identically to untreated T-cells except that they were resistant to infection by HIV. ZFN treated primary CD4 T-cells and transformed CD4 cell lines resisted infection with R5-tropic HIV (virus that uses the CCR5 co-receptor to enter cells), resulting in enrichment of ZFN-generated CCR5-disrupted cells in the population upon long-term exposure to virus (>50 days). Importantly, in the presence of HIV, ZFN-modified CD4 T-cells also preferentially expanded in a mouse model. The modified cells were infused into mice that lack a normal immune system and thus do not reject human cells. After 33 days, the mice were sacrificed and analyzed for the presence of ZFN-modified cells. Researchers determined that ZFN-modified cells engrafted normally in the mouse and that the proportion of modified cells present at the end of the experiment was greater than two to three fold higher in mice in the presence of HIV infection (p=0.008). In additional experiments, it was determined that 50 days after infection, mice given the ZFN-modified cells had increased numbers of CD4 cells and a statistically significant reduction in viral load in their peripheral blood (P<0.001) compared to mice given control cells. These data suggest that, in the presence of HIV, the ZFN-modified cells have a selective advantage allowing them to evade infection and destruction.
About HIV/AIDS and CCR5
HIV stands for Human Immunodeficiency Virus. HIV infection kills or impairs cells of the immune system progressively destroying the body’s ability to fight infections and certain AIDS (Acquired Immune Deficiency Syndrome). Individuals diagnosed with AIDS are susceptible to life-threatening diseases called opportunistic infections, which are caused by microbes that usually do not cause illness in healthy individuals. According to UNAIDS/WHO, over 2.7 million people were infected with HIV in 2007. There are now over 33 million people living with HIV and AIDS worldwide.
About Sangamo
Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP Therapeutic(TM) development program is currently in Phase 2 clinical trials for evaluation of safety and clinical effect in patients with diabetic neuropathy and ALS. Sangamo also has a Phase 1 clinical trial to evaluate safety and clinical effect of a ZFP Therapeutic approach for the treatment of HIV/AIDS. Other therapeutic development programs are focused on cancer, neuropathic pain, nerve regeneration, Parkinson’s disease and monogenic diseases. Sangamo’s core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN) for gene modification. Sangamo has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences, Sigma-Aldrich Corporation and several companies applying its ZFP technology to engineer cell lines for the production of protein pharmaceuticals.
This press release may contain forward-looking statements based on Sangamo’s current expectations. These forward-looking statements include, without limitation, references to clinical trials of SB-728-T, the potential for further study and development of SB-728-T for the treatment of HIV/AIDS, the research and development of novel ZFP TFs and ZFNs as ZFP Therapeutics, applications of Sangamo’s ZFP TF technology platform, strategic partnerships with collaborators and clinical trials of ZFP Therapeutics. Actual results may differ materially from these forward-looking statements due to a number of factors, including but not limited to, technological challenges, uncertainties relating to the initiation and completion of stages of ZFP Therapeutic clinical trials for Sangamo’s HIV/AIDS therapeutic development program, Sangamo’s ability to develop commercially viable products and technological developments by our competitors. See Sangamo’s SEC filings, and in particular, the risk factors described in Sangamo’s Annual Report on Form 10-K and its most recent quarterly report on Form 10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.
Source: Sangamo BioSciences, Inc