FAP-2286 — A Targeted Radionuclide Therapy With Broad Potential in the Treatment of Solid Tumors
Clovis Oncology’s lead targeted Short for radioactive nuclide, a radionuclide is an unstable atom that emits radioactive particles in the form of alpha, beta, or gamma particles. therapy candidate, FAP-2286, has the potential for broad clinical utility by targeting an array of solid tumors – a potential “pan-cancer” approach.
Fibroblast Activation Protein — A Ubiquitous Target
A common misconception is that tumors are uniform masses comprised of cancerous cells. In fact, tumors are highly complex tissues made up of many different components, including cancer cells, infiltrating immune cells, fibroblasts, interstitial components, as well as supporting vascular tissue that provides blood flow to the tumor. This complex arrangement of non-cancerous cells, signaling molecules and supporting extracellular matrix associated with the mass of cancerous cells is known as the The tumor microenvironment is the environment surrounding the mass of cancerous tumor cells, including blood vessels, immune cells, cancer associated fibroblasts, signaling molecules and the extracellular matrix. The tumor is supported by its surrounding microenvironment.. Some of the most important cancer therapeutic targets are elements of the tumor microenvironment, and not cancer cells themselves.
Cancer associated fibroblasts (CAF) are cells that occur abundantly within solid tumors. In healthy tissues, fibroblast cells contribute to the extracellular matrix, collagen and structural framework for healthy tissues, and play a critical role in wound healing. However, when associated with cancer cells, they become CAFs and take on a more deleterious role, secreting tumor growth factors and suppressing the body’s immune response to the tumor.
A cell-surface protein that is highly expressed in cancer associated fibroblasts and cancer cells. (FAP) is a cell surface protein that is found in a wide range of cancers, including breast, lung, colorectal and pancreatic cancers. FAP is highly expressed on the surface of CAFs. FAP is also expressed on the cell surface of some tumor cells.
In the fibroblast cells of healthy tissues, FAP expression is very limited, which reduces the potential for FAP-2286 to target normal, healthy tissues. When healthy fibroblasts convert to CAFs, FAP becomes highly expressed on the cell surface. The high levels of FAP expression observed on CAFs and tumor cells across multiple solid tumor types make FAP a compelling target to explore in clinical development.
FAP-2286 — A Pan-cancer targeted radionuclide therapy candidate
FAP-2286, Clovis Oncology’s lead targeted radionuclide therapy candidate, links the isotope A radioactive isotope of Lutetium, which is a beta particle emitting radionuclide. with a peptide designed to have a high binding affinity for FAP. Preclinical studies have shown that when administered, FAP-2286 is intended to potently and selectively bind to FAP on the surface of CAFs and tumor cells and deliver the radiation-emitting radionuclide in a highly targeted and controlled manner. Once bound, FAP-2286 induces DNA damage and cell death of FAP-positive CAFs and neighboring tumor cells and in some tumor types, FAP-2286 accumulates directly in the tumor, inducing cell death.
Beyond FAP-2286’s potential as a monotherapy, it may also offer the potential to enhance existing cancer treatments. For example, FAP-2286 may restore anti-tumor immune responses in the body through suppression of CAF populations. In combination with the checkpoint inhibitor PD-(L)1, FAP-2286’s mechanism of action might overcome resistant cancers, and potentially allow cancer to be treated once again with immunotherapy.
Potential as an Imaging Agent
To further increase its potential clinical utility, FAP-2286 is being developed as a theranostic, which may potentially be used as a therapeutic or imaging agent. The companion imaging agent can be used to confirm the presence of a target and whether a patient may be appropriate for therapy.
For FAP-2286 the companion imaging agent is achieved by replacing the lutetium-177 radionuclide with gallium-68. An imaging agent can also be a standalone imaging product used to diagnose and stage cancer.
LuMIERE — FAP-2286 Phase 1/2 Clinical Trial
LuMIERE, Clovis Oncology’s first radiopharmaceutical clinical study, is a Phase 1/2 trial of FAP-2286 as a treatment and imaging agent in a variety of solid tumors. The Phase 1 portion of the LuMIERE clinical study will assess safety and identify the recommended Phase 2 dose of lutetium-177 labeled FAP-2286 (177Lu-FAP-2286) and is currently ongoing. Once the recommended Phase 2 dose is determined, Phase 2 expansion cohorts are planned in multiple tumor types. Gallium-68 labeled FAP-2286 (68Ga-FAP-2286) will be utilized as an FAP-targeted imaging agent to identify patients eligible for treatment in the study. Data from Phase 1 as well as data from an ongoing investigator-initiated trial (IIT) at University of California San Francisco (NCT04621435, Phase 1 single-arm imaging study with dosimetry and 68Ga-FAP-2286 imaging cohorts using 68Ga-FAP-2286 in patients with solid tumors) will be used to inform additional tumor type selection for the LuMIERE Phase 2 expansion cohorts.
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