ADC Reviews

A review of the research progress of CSF-1R drugs


Immunotherapy, a targeted approach to the treatment of malignant tumors, has shown great potential by using the autoimmune system to fight tumor cells. Immunotherapy includes monoclonal antibody immune checkpoint inhibitors, therapeutic antibodies, cell therapy, etc., with excellent efficacy and innovation. After the widespread use and success of immune checkpoint inhibition (ICI) therapies targeting PD-1, PD-L1 and CTLA-4, the third phase of immunotherapy for cancer treatment has officially arrived.

However, in the course of treatment, a considerable number of cancer patients still do not respond to or develop resistance to ICI treatment, so scientists have been working to explore new immune targets, including macrophage-targeted drugs. There are many potential targets for targeting macrophages, and the main targets with rapid clinical progress include: CSF-1R, CD47, CD40, macrophage microenvironment chemokines, etc.

So far, very few drugs that directly target macrophages have been approved by the FDA for clinical trials, and no related products have been marketed for the time being. Recently, the FDA approved a Phase I study of ABSK021, a highly selective CSF-1R inhibitor, by Abbisko Therapeutics Co., Ltd. (Hong Kong Stock Exchange: 2256.HK). To assess safety, tolerability and pharmacokinetics in patients with advanced solid tumors.

CSF-1R signaling pathway
Colony-stimulating factor-1 (CSF-1), also known as macrophage colony-stimulating factor, is one of the most common pro-inflammatory cytokines responsible for various inflammatory diseases. It has a significant role in the development and progression of osteoarthritis, cancer and other autoimmune diseases. CSF-1 acts by binding to a receptor called the colony-stimulating factor 1 receptor (CSF-1R), also known as c-FMS, leading to a cascade of signaling pathways that lead to cell proliferation and differentiation. While CSF-1R appears to be the only receptor for CSF-1, IL-34 also binds the receptor protein-tyrosine phosphatase-zeta (RPTP-zeta) and the ligand expression pattern is different.

CSF-1R/c-FMS is overexpressed in macrophages in many tumors and, therefore, has been used as a promising drug target for the treatment of cancer and inflammatory diseases. Several CSF-1R/c-FMS inhibitors, such as ABT-869, Imatinib, AG013736, JNJ-40346527, PLX3397, DCC-3014, and Ki20227, have been investigated for the treatment of these diseases.

CSF-1R inhibitors block disease progression by binding to CSF-1R and preventing active cells from signaling from the body. In recent years, scientists have explored a series of CSF-1R targeted drugs based on this target, and the research status of related products is mostly clinical phase I.

CSF-1R targeted drugs
Strategies to target CSF-1R fall into two categories. Either a macromolecule antibody can be used to target its CSF-1 ligand, or CSF-1R receptor, or a small molecule can be designed to target the kinase active region. Clinical studies have shown that the current clinical leaders are Roche’s drug Emactuzumab (RG7155), Pexidartinib (PLX-3397), FivePrime’s Cabiralizumab (FPA008, clinical phase II, the current fastest progress), Treasure Ship Bio’s BC006, Heyu Pharmaceutical ABSK021 and Hercynian New Drug’s C019199, etc.

Emactuzumab is a CSF-1R monoclonal antibody developed by Roche. Imatinib was used in previous studies to try this in patients with tenosynovial giant cell tumor (TCGT). However, due to the weak CSF-1R activity of imatinib, the overall response rate was higher than that of imatinib. Low, only 19%. However, Roche’s CSF-1R antibody Emactuzumab has extremely high activity, and preclinical tests have also shown that it can effectively inhibit M2 type macrophages and promote the increase of T cell activity. At the same time, in the clinical trial of TCGT, it also showed a positive response rate of 86% (24/28). Two of these patients achieved complete remission, further demonstrating the targetability of the CSF-1/CSF-1R signaling pathway. Of course, Emactuzumab also has certain side effects, mainly including facial edema (periorbital edema), fatigue and itching.

The small molecule CSF-1R kinase inhibitor PLX-3397 also showed excellent clinical data in the TCGT patient population, and the ORR of PLX-3397 reached 52% (12/23). The toxicities associated with PLX-3397 mainly included fatigue, hair color change (74%), nausea, dysgeusia, and periorbital edema. However, studies have not yet fully determined which toxicities are directly related to targeting CSF-1R. Although PLX-3397 has good selectivity, high reported activity, and reasonably good PK, clinical trials have used doses up to 1000 mg/day. Some experts also suspect that its activity may not be as high as it has been reported. Compared with the higher response rate and less toxicity of the CSF-1R antibody, 61% of clinical patients with PLX-3397 also required dose reduction to reduce toxicity.

In addition to TCGT, clinical trials of CSF-1R alone in many other solid tumors are also underway, but the preliminary data obtained so far are not very positive, and the effect of single use is limited. The targeting potential of CSF-1R favors combination therapy, as is the case with IDO inhibitors. Whether CSF-1R can achieve the combined effect of IDO remains to be further observed and studied.

BC006 monoclonal antibody is a humanized monoclonal antibody developed by Baochuan Biotechnology, which mainly acts on the CSF-1R target on the surface of the macrophage system. Binding of CSF-1R/CSF-1 induces differentiation of macrophages. BC006 inhibits the mutation of macrophages by blocking the CSF-1R signaling pathway, thereby reducing the number of M2-like macrophages in the tumor environment, restoring macrophage function, and producing anti-tumor effects.

Currently, West China Hospital is conducting a Phase I clinical study of BC006, the first in a human, open-label, exploratory Phase I clinical study, including dose escalation (Ia) and dose expansion (Ib) phases. To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of BC006 in giant cell tumor of the tendon sheath (GCTTS) and other advanced solid tumors.
At present, there are also research data showing that BC006 has shown significant efficacy in animal models in the study of idiopathic pulmonary fibrosis (IPF). As the first CSF-1R antibody drug in China, BC006 is expected to address the unmet medical needs of various solid tumors, hematological tumors, bone and joint diseases and other diseases by regulating the pharmacological mechanism of macrophage activity, bringing new opportunities and develop.

C019199 is a CSF-1R inhibitor independently developed by Haixi New Drug, which also has inhibitory effect on VEGFR2. In the mouse allograft model, the drug showed obvious anti-tumor activity against colon cancer, melanoma, breast cancer, pancreatic cancer, etc., and showed a synergistic effect in combination with PD-1 monoclonal antibody. It has been approved for clinical use in China and is currently undergoing Phase I clinical trials (CTR20202045) for the treatment of colorectal cancer, melanoma, pancreatic cancer, and giant cell tumor of the tendon sheath.

ABSK021 is a new oral, highly selective and highly active CSF-1R small molecule inhibitor independently developed by Heyu Pharma. By regulating tumor-associated macrophages and other brain tumor immune cells, it changes the tumor microenvironment, relieves tumor immunosuppression, and produces a good tumor suppressor function. Preliminary clinical data show that ABSK021 has good tolerability, pharmacokinetic properties and effective inhibition of the target.

ABSK021 is also the first CSF-1R inhibitor independently developed and promoted by a Chinese company. It has previously completed a Phase 1a dose escalation trial in the United States and demonstrated good safety and PK/PD properties (NCT04192344).

Cabiralizumab (FPA008), an anti-CSF-1R antibody developed by FivePrime (acquired by Amgen in 2021), can lead to depletion of tumor-associated macrophages (TAMs), and one of PD-1 resistance may be tumor microphages There are immunosuppressive mechanisms similar to TAM in the environment. Therefore, there is a certain theoretical basis for further relieving tumor immunosuppression by inhibiting CSF1R. Preclinical studies have shown that CSF-1R and PD-1 inhibitors have synergistic effects.

At present, a phase II clinical trial of FPA008 is underway to explore the efficacy of Cabiralizumab and Nivolumab with or without chemotherapy in the treatment of advanced pancreatic cancer. It is currently the most advanced in the development of drugs targeting CSF-1R. The chemotherapy drugs in the experiment included paclitaxel, gemcitabine, irinotecan liposomal injection or the FOLFIRINOX regimen. The study plans to enroll 160 patients and the primary endpoint is progression-free survival (NCT03336216).

As an immunotherapy target for tumor immunotherapy, CSF-1R participates in the occurrence of solid tumors by regulating the role of TAMs in the tumor microenvironment. According to the current research progress, CSF-1R has a good prospect in the anti-tumor immune response, not only with single-agent therapy, but also combined with immunotherapy, chemotherapy or targeted therapy. Although there is no CSF-1R targeting antibody drug approved for marketing so far, there are still reasons to believe that we will obtain more active and comprehensive clinical data in future research to effectively improve the therapeutic effect and provide more cancer patients. Offers new treatment options, new treatment possibilities.