Description:
Designing universal donor B cells that will respond to antigen independently of T cell boost
Methods to link CD40 signaling to antigen binding independently of CD40L binding in order to potentiate B-cell responses.
Vaccines increase immunity against infections by stimulating B cells to produce antibodies against the infectious agent. In addition to infections, antibodies are also useful as treatment for different autoimmune conditions, and cancer. To mount a potent B cell response, interaction between CD40 (expressed on the surface of B cells) and CD40 ligand (CD40L; expressed on the surface of CD4+ T cells) is typically required for expansion, survival and differentiation of the B cells. B cell dependence on T cell interaction via MHC presentation also limits development of universal donor B cells for broader therapeutic applicability. To overcome this, Fred Hutchinson Cancer Center researchers have developed a method to genetically modify B cells to express fusion proteins that link extracellular antigen binding domains to CD40 signaling domain. This allows CD40 signaling activation upon antigen binding, independently of interaction with CD40L on T cells. Two approaches to link CD40 signaling to antigen binding have been developed: (a) Linking CD40 signaling to B cell receptor (BCR) signaling and (b) Linking CD40 signaling domain to engineered extracellular antigen binding domains.
<ul>
<li>Enhancing responses of B cells engineered to combat common respiratory viruses (e.g., RSV, HMPV, influenza, etc.)</li>
<li>Enhancing responses of B cells engineered to combat other viral (e.g., HIV, CMV, EBV, hepatitis C, herpes simplex, etc.) or bacterial (e.g., Bordetella, clostridium difficile, etc.) infections</li>
<li>Potentiating therapeutic response of B cells producing antibodies for autoimmune diseases and cancer</li>
</ul>
<ul>
<li>Improves response activity of B cells independent of CD40L interaction and thus leads to a greater response to a vaccine or treatment</li>
<li>Obviates the need for MHC II interaction between T cell and B cell (either by surpassing CD40 – CD40L interaction, or by a genetically engineered deletion of MHC II molecules in B cells) allowing for ‘universal’ donor B cell therapeutics</li>
</ul>
Given the broad applicability of the technology, the market potential is promising. The global respiratory virus infection drugs market is expected to exceed a value of US$ 82.8 billion by 2030. Even though the therapeutic modalities are fragmented, the global autoimmune disease therapeutics market was worth $ 54.8 B (USD) in 2021 and expected to grow at a CAGR of 12.9%. Similarly, the global HIV therapeutics market is expected to surpass $ 40.3 B (USD) by 2030.
<ul>
<li>Justin Taylor Ph.D.; Associate Professor - Vaccine and Infectious Disease Division</li>
</ul>
Preclinical <em>in vitro</em>
WO/2022/170271 A2
20-143_Taylor_Linking CD40 signaling to Ag_NCS_FHCC_Final.pdf
CD40 | CD40 Ligand (CD40L) | B cell| antibody engineering | infectious deisease | cancer | autoimmune | engineered monoclonal antibody (emAB) | RSV | HIV | influenza | CMV | EBV | Herpes simplex virus | MHC II | universal donor | B cell therapeutic |
Linking-CD40-signaling-to-Ag-20-143