Multimeric Biotherapeutics (Multimeric) is an early-stage biotech company that was founded to spinout technology developed at UC San Diego by its scientific founder, Richard S. Kornbluth, MD, PhD, Associate Professor of Medicine. The company’s product development focus is based on a technology for expressing TNF superfamily (TNFSF) molecules as multimeric, many-trimer soluble proteins with markedly enhanced activity. Molecules with 4 TNFSF trimers are called the “UltraLigands™” and molecules with 2 TNFSF trimers are called the “MegaLigands™.” The lead compound is UltraCD40L™ (SP-D-CD40L), a 4-trimer form of CD40 ligand (CD40L) that stimulates the immune system. A similar protein, MegaCD40L™ (Acrp30-CD40L), is a 2-trimer molecule that is already in use by research laboratories around the world as a powerful immune stimulating agent. Multimeric has exclusive worldwide licenses to the therapeutic uses of the TNFSF multimerization technology, which can also be applied to the other 18 proteins in the TNF superfamily for use in cancer immunotherapy, vaccines, transplantation, and regenerative medicine. For its first clinical trial, Multimeric is planning a breakthrough cancer treatment that combines genetic information obtained from a patient’s own tumor cells with an UltraCD40L™-enabled strategy that generates anti-tumor T lymphocytes for administration back into the patient’s body to fight the tumor.
Receptor clustering is needed for many TNF SuperFamily receptors to transmit a full signal
The following TNFSF receptors are stimulated by many trimer forms of their respective ligands but not by 1-trimer forms: CD40; TNFR2; Fas; 4-1BB; DR3; DR5; TACI; and GITR.
Production of multi-trimer forms of soluble TNFSFs using multimerization scaffolds
MultimericBio’s UltraTNFSFs are produced by genetically fusing the extracellular TNFSF domain with the body of a spontaneously multimerizing scaffold protein. Surfactant protein D (SP-D) is ideal because it is a self-assembling protein with four trimeric arms. For the SP-D versions of the UltraLigands, the protein is first synthesized within cells as a single polypeptide chain.
- Figure 1: Each chain forms a trimeric “arm” within the cell.
- Figure 2: Four arms come together at a “hub” to make a molecule with four TNFSF trimers that is then secreted.
- Figure 3: Further stacking at the hub can create higher order multimers of TNFSFs.
- The UltraLigands are soluble, many trimer proteins that act like the membrane forms of TNFSFs.
One-trimer CD40L has little or no activity on resting cells in vitro. In contrast, UltraCD40L (i.e., 4-trimer SP-D-CD40L) is strongly activating. Similar results were shown for SP-D-CD40L by Haswell, Glennie, and Al-Shamkhani (Eur J Immunol. 31:3094-3100, 2001) and analogous data were presented for Acrp30-FasL by Holler et al. in the group of Schneider and Tschopp (Mol Cellular Biol 23:1428-1440, 2003). Because the many trimer Ultra-TNFSFs cluster their receptors in responding cells, they have activities similar to the membrane forms of the TNFSFs, yet they can diffuse through tissues as soluble proteins.
Richard S. Kornbluth, MD, PhD – Co-Founder, President, and CSO
David A. Roth, PhD – Co-Founder and COO
Marc Hertz, PhD – Co-Founder and Board Chair
Mariusz Stempniak, PhD – Principal Scientist
Richard S. Kornbluth, MD, PhD
Associate Professor, Medicine
School of Medicine