This week, during the 10th annual Biotech Showcase™ conference in San Francisco, Siamab will presents updates from its proprietary technology platform and its development pipeline, including the ST1, the company’s lead monoclonal antibody (mAb) therapeutic.
ST1 is an antibody-drug conjugate or ADC for the treatment of solid tumors expressing the Sialyl-Thomsen-nouveau antigen (STn or Sialyl-Tn, also known as CD175s), a cancer specific antigen that is expressed on the cell surface of carcinomas including.ovarian, colon, prostate, and pancreatic tumors but is rarely present in normal tissue, in late stage pre-clinical development.
The investigational antibody-drug conjugates includes a Sialyl-Thomsen-nouveau antigen conjugated to monomethyl auristatin E (MMAE). These ADCs demonstrated in vitro efficacy in STn-expressing cell lines and significant tumor growth inhibition in STn-expressing tumor xenograft cancer models with no evidence of overt toxicity.
In addition to updated information about the company’s antibody-drug conjugates, Jeff Behrens, Siamab’s president and chief executive officer, will also present new data on targeting STn+ myeloid-derived suppressor cells (MDSCs), major regulators of the tumor anti-immune response that act by suppressing T cells.
Siamab has for the first time identified and utilized the presence of STn on MDSCs to target and deplete MDSCs in vivo, providing a potential new therapeutic approach for the treatment of solid tumors.
“We look forward to presenting an overview of our glycan-targeting platform to treat solid tumors,” Behrens said.
“We will be focusing on promising new data from the ST1 program that points to STn+ MDSCs as an exciting and untapped immune-oncology target. ST1 has demonstrated excellent efficacy and safety in multiple IND-enabling tumor models as a direct anti-cancer therapy, and it may also have the potential to deplete MDSCs, which are known to be potent suppressors of tumor immunity,” he added.
Emerging set of tumor antigens
TACAs are an emerging set of tumor antigens that are implicated in immune suppression, chemoresistance and a cancer stem cell (CSC) phenotype. The elevated presence of STn—a key TACA observed in a number of solid tumors, including ovarian, prostate, pancreatic, gastric, and colon—is associated with metastatic disease, poor prognosis, and reduced overall survival.
Elevation of STn expression is linked to chemotherapy resistance and enables tumors to evade the host immune system. In addition, STn is expressed on multiple biomarkers including the CSC biomarkers CD44 and MUC1, which reside on both CSCs and mature malignant cells in some cancer types.
Siamab’s proprietary technology platform enables the development of highly specific mAb therapeutics, including ADCs, bi-specific antibodies and CAR-T cell therapies, targeting cancer cell surface glycans called tumor-associated carbohydrate antigens (TACAs).
Historically, TACAs have been challenging targets for antibody therapeutics. STn expression has been linked to innate immune suppression, a chemoresistant phenotype, metastasis, and poor prognosis. Previous attempts to target this antigen in the clinic with synthetic glycan vaccines proved safe but lacked efficacy.
Now, for the first time, scientists at Siamab have developed highly selective humanized monoclonal antibodies and antibody-drug conjugates (ADCs) targeting TACAs, such as STn.
Sequence homology across all anti-STn antibodies was observed in both heavy and light chains, and hot spots for hypermutation were identified. These antibodies were selected using our glycan microarray that enriches for candidates whose binding is protein independent, highly selective and demonstrates exceptional affinity.
Safety and efficacy
Siamab scientists have demonstrated the safety and efficacy of their anti-STn antibody therapeutic in multiple preclinical studies. The company’s lead ST1 Antibody-drug Conjugate has shown to inhibit tumor progression in cell line-derived and patient-derived xenograft (PDX) mouse models of ovarian and pancreatic cancer, with complete regression observed in some treatment arms.
In addition, preclinical evaluation has demonstrated the compound’s safety across species, including in non-human primates.
Siamab is also utilizing STn-selective antibodies to develop both tissue- and serum-based biomarker assays with the potential to become companion diagnostics for both the stratification of patients as well as tools for assessing the pharmacodynamics action of the anti-STn therapeutic in the clinic.