There is a growing need for targeted cancer treatments that are highly effective and pose minimal side effects. In recent years, antibodies are taking center stage as functional therapeutics with the potential to deliver on both these requirements. Antibodies are also being tested for strengthening or restoring the immune system’s inherent ability to fight cancer.
Immune Biosolutions’ Nebula Antibody Platform is perfectly positioned to address some core challenges in the development of antibody-based cancer therapeutics. G-protein-coupled receptors (GPCRs) for example, are an important and historically-difficult cancer target that we have chosen to tackle initially.
GPCRs are transmembrane receptors which activate a number of signaling pathways implicated in cell growth and behavior. As such, they are the target of many cancer drugs on the market today. Anti-GPCR antibodies have been contemplated for many years as possible therapeutic agents as they are thought to have more efficacy, higher specificity and decreased side effects compared to their small molecule counterparts. However, therapeutic antibody discovery efforts have been hindered by multiple technical obstacles including: the lack of structural data; the highly variable structure and limited number of exposed epitopes in GPCR extracellular regions; an inability to produce homogeneous and functional GPCR antigen preparations; the inefficiency of existing GPCR antibody screening tools; and the highly conserved homology of GPCRs among mammalian species.
With our Nebula Antibody Platform, we have overcome several of these barriers to develop antibody candidates against the following GPCRs:
Neurotensin receptor 1 (NTSR1) is a GPCR that, once activated by its natural ligand (neurotensin), induces several signaling pathways involved in cell proliferation, survival, migration, and invasion. NTSR1 overexpression has been implicated in cancer cell growth and correlated with decreased overall survival in patients.
Immune Biosolutions is developing antagonistic antibodies to block NTSR1-induced onco pathways in cancer cells. To date, we have designed Spatial Peptide antigens that mimic ideal NTSR1 epitopes and used these to immunize chickens. We are currently testing several high-affinity batch-humanized binders from a derived scFv library in functional and efficacy assays. Once validated in vitro, the candidates will be fully humanized and tested for efficacy and safety in vivo (planned for 2019).
Bradykinin receptor B1 (BKRB1 or B1R) is a GPCR whose expression is induced mainly in the context of inflammation and cancer. Similar to our NTSR1 program, we are currently developing antagonistic antibodies to block B1R-induced onco-dependent pathways in cancer cells. Using only the B1R DNA sequence and our proprietary algorithms, we have already designed spatial peptides that mimic ideal epitopes in B1R and used these to immunize chickens. Several high-potential candidates have been selected from an antibody panel derived from immunized chickens’ lymphoid glands and a few have undergone in vitro validation. Our preliminary results demonstrate a reduction in cancer cell proliferation upon two weeks of exposure to these candidates. Once validated in vitro, all the high-potential candidates will be fully humanized and tested for efficacy and safety in vivo (planned for 2019).
Purinergic receptor P2Y6 is a GPCR with broad tissue distribution that is involved mainly in the inflammatory process. This receptor has been specifically implicated in colorectal cancer: activated P2Y6 induces cancer cell growth in vitro and knockout of P2Y6 in mice reduces the number and size of colorectal tumors. P2Y6 may also play a role in bacterial infection and inflammation of the GI tract.
Immune Biosolutions is developing P2Y6 antagonistic antibodies that specifically target the receptor in the GI tract. These candidates would present novel colorectal cancer or GI infection treatments while posing minimal systemic side effects. Using our proprietary algorithms and the P2Y6 DNA sequence, we have already designed antigenic P2Y6 Spatial Peptides and used these to immunize chickens. Several highly specific polyclonal and recombinant antibodies have been identified and future work will include further selection and validation of recombinant antibody candidates.