Tumor vascularization involves angiogenesis, which is the development of new vasculature generated from existing blood vessels or formed by circulating endothelial cells (ECs). Angiogenesis is required for the growth of tumors and is essential for neoplastic progression of tumor cells. In recent years antibody drugs such as Avastin (bevacizumab) of Genentech/Roche and Cyramza (ramucirumab) of Eli Lilly have been marketed as anti-angiogenesis drugs with significant success. A product of over $5 billion in 2020 global sales, Avastin is a humanized antibody and an inhibitor of vascular endothelial growth factor (VEGF), one of the key signaling molecules for angiogenesis. Avastin is used worldwide in the treatment of colorectal, brain, lung and kidney cancer. Eli Lilly’s Cyramza (ramucirumab), which is a fully human antibody against VEGF receptor, VEGFR2, with 2020 sales over $1 billion is used for the treatment of stomach and NSCLC.
In addition to angiogenesis, many solid tumors may also assemble vascular channels derived from and lined by tumor cells themselves, rather than ECs, a process known as vasculogenic mimicry (VM). VM channels can anastamose with ’normal’ blood vessels and serve as conduits for metabolic supply of nutrients. VM is distinct from angiogenesis. Originally described in ocular and cutaneous melanoma, VM is seen in many solid tumors including breast, ovarian, lung cancers and glioblastoma. VM related channels formed from tumor cells might develop resistance to chemotherapy, radiation and anti-angiogenic therapy due to their inherent genetic instability, and VM may also contribute to elevated oncotic pressure within tumors that impairs drug delivery. VM has also been linked to tumor aggressiveness and metastasis and to a cancer stem cell like phenotype. In a recent meta-analysis of more than 3,000 cancer patients involving 15 types of cancer, 5year overall survival in VM-negative patients was almost double that seen for VM-positive patients. Although VM may play a critical role in supporting cancer growth, many angiogenesis inhibitors in clinical use have little/no effect on VM.
We have been developing antibody-based fusion therapeutics that are fully biological in nature which provide combined inhibition of both angiogenesis and VM. Our drugs are expected to provide more potent means of inhibiting cancer growth and metastasis in clinical settings. The most advanced candidates in our pipeline are tumor-targeted fusion proteins generated from our A-TAP (Antibody-Targeted Anti-vasculogenic Payload) platform. A-TAP involves linking of a tumor targeted antibody with a more potent variant of endostatin, endostatin-P125A, as an anti-vasculogenic biological payload.
"We have to ask ourselves whether medicine is to remain a humanitarian and respected profession or a new but depersonalized science in the service of prolonging life rather than diminishing human suffering".
- Elisabeth KüBler-Ross