The University of Zurich has granted Humanigen an exclusive license for the prevention of GvHD (Graft-versus-Host Disease) through GM-CSF Neutralization. This deal helps Humanigen expand its extensive intellectual property portfolio to include prevention of Graft-verus-host Disease while strengthening its leadership position and platform in granulocyte macrophage-colony stimulating factor (GM-CSF) neutralization to include allogeneic hematopoietic stem cell therapy (HSCT). The GM-CSF neutralization represents the potential to break the efficacy/toxicity linkage associated with allogeneic HSCT.
What is Graft-versus-Host Disease or GvHD?
In GvHD, the donated bone marrow or stem cells view the recipient’s body as foreign, and the donated cells/bone marrow attack the body. The two types of GvHD are acute and chronic. This is a problem that stem cell therapy drug companies seek to overcome.
What is GM-CSF Neutralization?
Colony-stimulating factor 2 (CSF2) is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that function as a cytokine called sargramostim and molgramostim. Unlike granulocyte colony-stimulating factor, which specifically promotes neutrophil proliferation and maturation, GM-CSF affects more cell types, especially macrophages and eosinophils.
Allogeneic hematopoietic stem cell therapy (HSCT).
Allogeneic HSCT is a potentially curative therapy for patients with hematological cancers. However, between 40-60% of patients who experience acute or chronic GvHD carry a 50% mortality rate. Donor-derived T cells are responsible for mediating the beneficial graft-versus leukemia (GvL) effect but have also been linking to destruction of healthy tissues such as the skin, gut, and liver, resulting in GvHD. Depleting donor grafts of T cells can prevent or reduce the risk of GvHD. However, the results in a reduced GvL effect and increased relapse rates. There is a significant unmet need for an agent that can uncouple the benefit of GvL effect from harmful GvHD and there are currently no approved agents for the prevention of GvHD.
What did University of Zurich License to Humanigen?
The University of Zurich licensed its technology used to prevent GvHD through GM-CSF neutralization. This technology was recently featured in a publication in Science Translational Medicine entitled “Graft-versus-Host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF-licensed myeloid cells.”
What does the License Cover?
An exclusive, global license covers various patient applications filed by the University of Zurich, which complements and broadens Humanigen’s leadership in the application of GM-CSF and expands Humanigen’s development platform to include improving the allogeneic HSCT.
More on the Technology
The authors demonstrated in the Science Translational Medicine article that in a murine model of GvHD, that donor T cell-derived GM-CSF drives GvHD through activation, expansion, and trafficking of myeloid cells but has no effect on GvL response. Naturalization of GM-CSF (by either using a neutralizing antibody or through GM-CSF gene knock-out) was able to uncouple the myeloid-mediated immunopathology, resulting in GvHD from the T cell-mediated control of leukemic cells (GvL).
This discovery offers a clear mechanistic proof-of-concept of neutralizing GM-CSF to prevent GvHD without compromising, and potentially improving, the GvP effect in patients undergoing allogeneic HSCT.
What About Humanigen?
Previously known as Kalabios, they have pioneered a strategy of neutralizing GM-CSF to improve the safety and efficacy of T cell therapies. Humanigen, Inc. is a biopharmaceutical company developing its Humaneered® proprietary monoclonal antibodies to address critical unmet needs in today’s most advanced cancer therapies. Humaneering is a patented proprietary technology for converting suboptimal antibodies (typically mouse antibodies) into human antibodies suitable for chronic therapies, in part, because of low immunogenicity. In completed clinical studies, the Humaneered® antibodies showed lower immunogenicity than is generally seen with competing human antibody approaches. This platform has the advantage of maintaining epitope specificity and increasing affinity.
Derived from the company’s Humaneered® platform, lenzilumab, ifabotuzumab, and HGEN005 are monoclonal antibodies with first-in-class mechanisms. Our lead monoclonal antibody asset, lenzilumab, targets soluble GM-CSF and has been demonstrated to significantly reduce neurotoxicity and prevent cytokine release syndrome associated with CAR-T cell treatment in a proprietary human xenograft model, while at the same time increasing CAR-T cell proliferation and effector functions. They are poised to begin clinical trials with lenzilumab for prophylaxis of neurotoxicity and cytokine release syndrome in combination with the leading CAR-T cell therapies. Ifabotuzumab, which targets Eph receptor A3 (EphA3), is being developed as a potential treatment for glioblastoma multiforme (GBM) and other deadly cancers, as well as a backbone for a novel CAR-T construct and as an antibody drug conjugate (ADC). HGEN005, which targets human epidermal growth factor-like modules containing mucin-like hormone receptor 1 (EMR1), has the potential to treat eosinophilic diseases and is being developed as a novel CAR-T construct for eosinophilic leukemia.