Improvement of Broadly HIV-Neutralizing Antibodies; Anti-HIV-1 Antibody VRC01.23 for Prevention or Treatment of HIV Infection

Scientists at NIAID have developed broadly neutralizing antibodies (bNAbs) with enhanced neutralizing activity against HIV-1. Specifically, previously unknown gp120 interactions with a newly elucidated quaternary receptor (CD4)-binding site in the HIV-1 envelope have been discovered by engrafting the extended heavy-chain framework region 3 (FR3) loop of VRC03 onto several potent bNAbs (including VRC01, VRC07 and N6).

Replication-Competent Adenovirus Type 4 SARS-CoV-2 Vaccines and Their Use

NIAID has produced recombinant adenovirus type 4 (Ad4), SARS-CoV-2 spike, vectors for administration to humans. These recombinant vaccines permit rapid development of high levels of neutralizing antibodies to SARS-CoV-2 in experimental animals. This vaccine is designed to improve the durability of the immune response by inducing mucosal and systemic immunity. Further, this system should be incredibly simple and efficient when producing vaccine at scale. This technology is available for licensing for commercial development in accordance with 35 U.S.C.

Humanized Murine Monoclonal Antibodies That Neutralize Type-1 Interferon (IFN) Activity

Interferons (IFNs) are a family of cytokines that function in response to an immune challenge such as a viral or bacterial infection. Type I IFNs are produced by immune cells (predominantly monocytes and dendritic cells) as well as fibroblasts and signal through a specific cell surface receptor complex (IFNAR) that consist of IFNAR1 and IFNAR2 chains. Type-I IFNs exert several common effects including antiviral, antiproliferative, and immunomodulatory activities. However, Type I IFNs also have pro-inflammatory effects, especially in the presence of TNF-a.

Replication-Competent Adenovirus Type-4 HIV Env Vaccines and Their Use

NIAID, IAVI, Emergent, and Scripps have developed two recombinant adenovirus type 4 (Ad4) vector-based vaccine candidates. These replicating Ad4 vector-based candidates have shown improved activity against tier 2 HIV-1 isolates in experimental animals. Tier 2 isolates are among the most prevalent in infected populations. The two candidates, Ad4-Env150KN and Ad4-Env145NFL, incorporate novel design features based on Ad4-EnvC150 (1086c). Specifically, the truncation of the cytoplasmic tail of Env increases cell surface expression and has resulted in improved antigenicity from both candidates.

Dual-Germline Antibody Engager Chimeric HIV–1 Immunogens

Despite four decades of intensive research, a safe and effective HIV-1 vaccine remains elusive due to the extreme difficulty in eliciting broadly neutralizing antibodies (bNAbs), which recognize and block HIV-1 from entering healthy cells. Only rare natural HIV-1 envelopes (Envs) promote the activation and expansion of naive B cells expressing unmutated germline antibodies of various bNAb lineages, but they typically do so for a single lineage for the same neutralization site.

HLA-class II-restricted T Cell Receptors for PIK3CA “Hotspot” Mutations, E545K and N345K

Summary: 

The National Cancer Institute (NCI) seeks co-development partners and/or licensees for a collection of T cell receptors (TCRs) that specifically target PIK3CA mutations to treat patients with tumors expressing these mutations in the context of HLA-DPA1*01:03:01, HLA-DPB1*04:01:01 or HLA-DRB1*04:01.

Description of Technology:

Next-Generation 5-HT-2B Serotonin-Receptor Antagonists for Anti-Fibrotic & Cardiopulmonary Therapy

This technology includes a family of small-molecule antagonists that selectively block the 5-HT2B serotonin receptor—an upstream driver of tissue-remodeling—to address fibrotic, cardiopulmonary and related disorders. Built on a conformationally-locked “(N)-methanocarba” nucleoside scaffold, the compounds show nanomolar potency, >30–400-fold selectivity over the closely related 5-HT2C receptor, and favorable oral bioavailability in rodents.

Bicistronic Chimeric Antigen Receptor (CAR) Constructs Targeting CD19 and CD20

CD19 and CD20 are promising targets for the treatment of B-Cell malignancies.  Unfortunately, some clinical studies have shown that there is a loss of CD19 or CD20 expression in various cases of lymphomas and leukemias, particularly after treatment with an agent that targets CD19 (e.g., anti-CD19 CAR-T). However, studies have shown that expression of one protein is retained when the other is lost. This suggests that a therapeutic with the ability to simultaneously target both CD19 and CD20 could represent a solution to the drawbacks of current therapies. 

Anti-SLAMF7 Chimeric Antigen Receptors

Immortalization of plasma cells leads to Multiple Myeloma (MM). Signaling Lymphocyte Activation Molecule F7 (SLAMF7) is highly expressed on the malignant plasma cells that constitute Multiple Myeloma. The expression of SLAMF7 by MM cells and lack of expression on nonhematologic cells makes SLAMF7 a promising target for chimeric antigen receptor (CAR) T cell therapies for the treatment of MM. 

Optimized Monospecific or Bicistronic Chimeric Antigen Receptor (CAR) Constructs Targeting CD19 and CD20

Patients with chemotherapy-refractory, diffuse large B-cell lymphoma (DLBCL) have poor prognoses. CD19 and CD20 are promising targets for the treatment of B-Cell malignancies. However, despite the initial promising results from anti-CD19 CAR therapy, only 30-35% of patients with DLBCL achieve remissions lasting longer than 2-3 years after anti-CD19 CAR T-cell therapy. Relapse and non-response are likely due to diminished CD19 expression after anti-CD19 therapy and low expression of CD19 in some lymphomas. 

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