Summary:
An HIV vaccine would have important and direct implications in our fight against AIDS and many types of cancer. HIV infection weakens the immune system and the body’s ability to eliminate abnormal cells, which can lead to cancers. HIV infection increases the risk for Kaposi sarcoma about 800-fold, Hodgkin lymphoma at least 10-fold, anal cancer at least 9-fold, non-Hodgkin lymphoma at least 7-fold, liver and lung cancer 3-4 fold, and, among women, cervical cancer at least 3-fold. Further, people that are co-infected with HIV and other viruses (for example, Human herpesvirus 8, Epstein Barr virus, Human papillomavirus, and Hepatitis B virus) are at an increased risk for cancers associated with those secondary viruses.

Despite more than two decades of intense research, only several broadly neutralizing anti-HIV-1 antibodies (bnAbs) have been identified and characterized. However, attempts to clinically elicit these antibodies, or antibodies that target the same epitopes, have failed. It is now known that these mature bnAbs are highly divergent from their putative predecessor germline antibodies. Recently, it was demonstrated that putative germline predecessors of some of these bnAbs do not bind to HIV-1 envelope glycoproteins (Envs). This and other findings indicate that currently used vaccine immunogens may not be capable of initiating immune responses leading to elicitation of bnAbs.

The NCI Center for Cancer Research (CCR) has developed a new technology whereby a primary immunogen can activate B cells that express putative germline predecessors of previously identified bnAbs. The inventor and his associates have identified one antigen that can bind a putative germline-like precursor of a known anti-HIV-1 bnAb. This invention is fully described in PCT Patent Publication Number WO/2010/042919 and is the subject of U.S. Patent Application Number PCT/US2010/060303 and HHS Reference Number E-322-2008/0.

Using this technology, possibly in combination with other not-yet-identified primary immunogens and probably in combination with Env-based immunogens, it may be possible to elicit bnAbs in a clinical setting. Necessary innovations include discovery of additional primary immunogens and in vivo immunogenic analyses of all primary immunogens using an appropriate animal model. Potentially necessary innovations include identification of intermediate B cells (intermediate in the maturation pathway of the mature bnAb) and the discovery/in vivo analyses of immunogens for these intermediate B cells.

Project Goals:
The ultimate goal of this topic is to accelerate the development of efficacious vaccines that can activate bnAb precursor germline B-cells and elicit anti-HIV-1 bnAbs. The short term goals of this topic are to test the in vivo immunogenic potential of the identified potential primary HIV immunogen in an innovative animal model and identify, and similarly analyze, one or more candidate primary immunogens. A mouse with human germline antibodies is an appropriate animal model to use.

This is an NIH TT (Technology Transfer) contract topic from the NCI. This is a new program whereby inventions from the NCI Intramural Research Program (Center for Cancer Research, CCR) are licensed to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this contract topic shall work closely with the NCI CCR inventor of this technology, who will provide putative germline predecessors of an anti-HIV bnAb, at least one candidate primary immunogen, mature bnAbs, Env-based putative immunogens, control antibodies, cell lines, reagents for binding and neutralization assays, as well as other reagents as needed. The inventor will provide assistance in a collaborative manner with reagents and discussions during the entire award period. Between the time this contract topic is published and the time an offeror submits a contract proposal for this topic, no contact will be allowed between the offeror and the NCI CCR inventor. However, a pre-submission public briefing and/or webinar will be given by NCI staff to explain in greater detail the technical and licensing aspects of this program (for further information, see http://sbir.cancer.gov/news/upcoming/). In addition, a list of relevant technical, invention, and licensing-related questions and answers (including those from the public briefing) will be posted, maintained, and updated online (http://sbir.cancer.gov/news/upcoming/) during this time period.

The awarded contractor will automatically be granted a royalty-free, non-exclusive license to use NIH-owned and patented background inventions only within the scope and term of the award. However, an SBIR offeror or SBIR contractor can apply for an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention. Offerors submitting an SBIR contract proposal in response to this topic are strongly encouraged to submit concurrently an application for a commercialization license to such background inventions. Under the NCI NIH TT program, the SBIR contract award process will be conducted in parallel with, but distinct from, the review of any applications for a commercialization license.

To apply for an exclusive or non-exclusive commercialization license to develop this NIH invention, an SBIR offeror or SBIR contractor must submit a license application to the NIH Licensing and Patenting Manager: Sally Hu, Ph.D., HuS@mail.nih.gov or (301) 435-5606. A license application and model license agreements are available at http://www.ott.nih.gov/pdfs/LicApp.pdf and http://www.ott.nih.gov/
forms_model_agreements/forms_model_agreements.aspx#LAP. Certain terms of the model license agreement are subject to negotiation. Please contact Dr. Hu with further questions.

This license application provides NIH with information about the potential licensee, some of the terms desired, and the potential licensee's plans for development and/or commercialization of the invention. License applications will be treated in accordance with Federal patent licensing regulations as provided in 37 CFR Part 404. A further description of the NIH licensing process is available at http://www.ott.nih.gov/licensing_royalties/intra_techlic.aspx. NIH will notify an SBIR offeror or SBIR contractor who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted.

Any invention developed by the contractor during the course of the NIH TT contract period of performance will be owned by the contractor subject to the terms of Section 8.5

Phase I activities and expected deliverables:

• Characterize in vitro the already identified putative primary immunogen for binding to human germline antibodies.
  
• Identify novel potential primary immunogens of bnAbs against HIV using putative germline predecessors of bnAbs.
  
• Perform in vitro characterization of the newly identified primary immunogens for binding to human germline antibodies.
  
• Obtain or generate and maintain mice that carry human germline antibody genes and that can be used as an in vivo model, e.g., can elicit high-affinity human antibodies by immunization.
  

Phase II activities and expected deliverables:
A Phase II proposal will typically/generally only be invited by NCI if the Phase I contractor has been granted a commercialization license via the NIH license application process described above.

• Analyze the immunogenic potential of the identified candidate primary immunogens in combination HIV envelope glycoprotein (Env)-based immunogens in the mouse animal model from Phase I.
  
• Characterize the antibody response elicited by the combination of primary immunogens and Env-based immunogens. Specifically, measure the binding titer of the serum against the immunogens used for immunization, and the neutralization titer of the serum against a panel of HIV-1 primary isolates from different clades provided by the inventor. Also isolate monoclonal antibodies at several time points, sequence them, analyze them in terms of somatic mutations and maturation stage, and characterize their binding to the immunogens used for immunization.
  
• Optimize immunization protocols and adjuvants for elicitation of antibodies with increased potency and breadth of neutralization.
  
• Provide optimized Standard Operating Procedure for immunization to the NCI.
  
• Recommend immunogens for further preclinical development based on their capability to elicit bnAbs. If this goal is not achieved, recommend immunogens for further research and development based on their ability to elicit antibodies that are intermediates in the maturation pathways of known bnAbs, providing a proof-of-concept for this approach.
  
• If this goal is achieved perform preclinical research in preparation for human phase I clinical trial.