An effective immune response requires VLA-4/VCAM-1 and LFA-1/ICAM-1 integrin-mediated cell adhesion.VLA-4 and LFA-1 are constitutively expressed on leukocytes and normally exist in a low affinity, inactive conformation. Induction by chemokines induces a high affinity, active conformation and inflammation induces VCAM-1 and ICAM-1 expression on target cells. Cell-cell adhesion mediated by VLA-4/VCAM-1 and LFA-1/ICAM-1 between naïve T cells and antigen presenting cells is essential for immune priming, and prolonged interaction between APCs and naïve T cells enhances T cell activation and memory. 7HP compounds are allosteric activators of VLA-4 and LFA-1 that may improve this T cell activation and memory, and are indicated to improve the effectiveness of both immune-oncology therapies and prophylactic T cell vaccines.
Prophylactic vaccines provide active acquired immunity against infectious diseases. Integrins α4β1 and αLβ2 are cell adhesion molecules that are essential for a productive immune response by promoting antigen presentation and immune priming. Prolonged integrin-mediated cell adhesion improves immunologic memory, which may improve the effectiveness of several infectious disease vaccines. 7HP compounds are currently being validated for influenza, coronavirus, and tuberculosis.
There exists a significant medical need to improve immune responses to influenza vaccines in the elderly. Adults >65 years of age have elevated risk of seasonal influenza-related hospitalizations and deaths. Antibody response and protection afforded by the vaccine are lower in elderly populations. Lack of vaccine effectiveness may be due to insufficient T cell priming, which can be addressed by the addition of 7HP compounds.
T cells and dendritic cells in the elderly have constitutively lower α4 integrin expression and attenuated induction of integrin ligand ICAM-1, respectively. Augmenting cell adhesion with 7HP349 may facilitate T cell activation and memory, potentially improving elderly patients’ response to influenza vaccines. We have shown in preclinical studies that 7HP349 as a systemic drug can augment influenza vaccine by increasing neutralizing antibody titers and seroconversion.
7HP technologies are designed to augment the naturally occurring adhesion cascade that facilitates cell movement from blood vessels into tissue. By specifically targeting certain cell adhesion molecules, in particular the integrin VLA-4, 7HP compounds can augment both the adhesion and migration of hematopoietic cells across simulated bone marrow endothelia and stroma.
Preclinical work has demonstrated that 7HP compounds:
Emerging "Immuno-Oncology" treatment strategies are focused on mobilizing the body’s natural immune defense mechanisms to clear malignant cells. Scientists have been able to generate highly specific immune cells that can directly adhere to and kill tumor cells, as well as drugs to unleash the immune system against cancer. However, a significant drawback of these current strategies remains the lack of efficient tumor localization of anti-tumor cells. This is because mobilized cancer fighting immune cells fail to migrate from the circulation to reach the site of tumor growth. The most important predictor of cancer related mortality for numerous solid tumors such as breast, colon, prostate and other cancers is the failure of immune cells to access the tumor.
Although emerging immuno-oncology products have been able to elicit unprecedented responses in cancers that are easily accessible to immune cells (eg. leukemia), solid tumors may be resistant to such therapies. 7 Hills is developing cost effective, safe therapeutics to overcome such resistance. Our lead compounds have the potential to increase the antitumor activity of numerous emerging cell-based immunotherapies, and enable the use of recently approved drugs to treat solid tumors that are currently refractory to therapy.
7HP compounds target validated cell adhesion pathways that are critical for T cell homing to specific tissues. They are the only known activators of both the VLA-4/VCAM-1 and LFA-1/ICAM-1 cell adhesion axes. Activation of these adhesion pathways could significantly increase the trafficking of endogenous effector lymphocytes (targets of checkpoint blockade therapeutics) or adoptively transferred effectors (like CAR-T cells) into solid tumors.
Pre-clinical studies have shown that 7HP lead compounds:
Umbilical cord blood transplantation is potentially curative option for a variety of hematologic cancers and genetic diseases. However, the use of cord blood transplant in adolescents and adults is limited by the number of hematopoietic stem cells homing and engrafting into the bone marrow microenvironment. This limited or delayed engraftment can lead to life threatening infections.