Abcuro Secures $155 Million Series B Financing to Advance First-in-Class KLRG1 Antibody for Autoimmune Diseases and Cancer

Recently, Abcuro, a biotechnology company supported by Sanofi, announced the completion of a $155 million oversubscribed Series B financing round. This round was co-led by Redmile Group and Bain Capital Life Sciences, with participation from RA Capital Management, Samsara BioCapital, Sanofi Ventures, New Leaf Ventures, Pontifax, and Tekla Capital Management.

The financing proceeds will be used to support the completion of the Phase 2/3 registration trial for the company’s core pipeline product ABC008, which is designed to evaluate the efficacy and safety of ABC008 in treating sporadic inclusion body myositis (IBM), as well as to further advance the development of other clinical programs. Previously, ABC008 has been granted orphan drug designation by the FDA.

Abcuro is a clinical-stage biotechnology company dedicated to developing immunotherapies for autoimmune diseases and cancer. Founded in 2015, its headquarters is now located in Newton, Massachusetts, USA. Novel antibodies are the focus of Abcuro’s research. In autoimmune diseases, while other companies have chosen to target CD25, CD2, CD52, and ICOS, Abcuro believes that KLRG1 is a better choice, as targeting KLRG1 drives the depletion of highly cytotoxic T cells.

Abcuro Chooses Inclusion Body Myositis as Testing Ground for This ConceptThis disease is caused by T cells attacking muscle fibers, leading to the loss of hand function and walking ability. In the long term, Abcuro plans to expand to other autoimmune diseases.

In 2021, Abcuro secured a $42 million Series A financing round led by Sanofi Ventures. Now, the company has received support from prominent investors such as RA Capital and Bain Capital Life Sciences in its Series B financing round, bringing the total funds raised across five previous rounds to $214.8 million.

Abcuro CEO Alex Martin said at the press conference, "With the support of such a strong group of investors, we will be able to complete our development programs for diseases with very few available treatment options."

T cells have a variety of biological functions, such as directly killing target cells, assisting or suppressing antibody production by B cells, responding to specific antigens and mitogens, and producing cytokines. They are the main force in the human immune system for resisting disease infections and tumor formation.

However, in the state of chronic viral infection and malignant tumors, effector T cells undergo changes such as exhaustion, dysfunction, and senescence. Under the long-term stimulation of chronic inflammatory pathogens and tumor antigens, effector T cells gradually lose their original abilities to recognize antigens, activate proliferation, and secrete interleukin-2 (IL-2). At the same time, they are suppressed by other regulatory T cells (Tregs). As a result, effector T cells lose their effector functions, fail to differentiate into memory T cells (TM), and cannot complete tumor cell killing or virus clearance, ultimately leading to immune escape.

Therefore, eliminating highly cytotoxic T cells that have lost normal immune response function could potentially treat a range of autoimmune diseases. Currently, non-selective T cell depletion therapies have shown good efficacy in treating various autoimmune diseases (such as multiple sclerosis and psoriasis). However, due to certain side effects and safety concerns, the scope of application of these therapies is limited.

Despite the challenges in the T-cell immunotherapy field, Abcuro has chosen to deeply cultivate this industry. Abcuro selectively targets highly cytotoxic T cells and has discovered the killer cell lectin-like receptor G1 (KLRG1), which is associated with the anti-tumor activity of T cells and natural killer (NK) cells.

KLRG1 is an immune checkpoint receptor encoded by the KLRG1 gene. It is an inhibitory lectin-like type II transmembrane receptor containing a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), and it mainly exists as a homodimeric molecule composed of two 30 kDa-38 kDa N-glycosylated subunits.

KLRG1 Expression Is Associated with Reduced Proliferation of Activated T Lymphocytes and Diminished Effector Functions of Activated NK Cells. E-, N-, and R-cadherins are homologous ligands of KLRG1, and their binding prevents Akt phosphorylation while increasing the expression of cell cycle inhibitors. They also activate the signaling molecules SHP-2 and SHIP-1, which in turn suppress NK cell effector functions and T cell proliferation.

Therefore, as an immune checkpoint receptor, KLRG1 can regulate the level of immune activation, acting as a "brake" in the body's immune response. Immune checkpoint inhibitors, on the other hand, bind to it to remove the "brake" function of the immune response, thereby activating the anti-tumor activity of highly cytotoxic T cells and NK cells.

KLRG1 has become a potential therapeutic target in immuno-oncology. Existing studies indicate that KLRG1 is selectively expressed on late-differentiated effector memory (TEM) and effector (TEMRA) T cells, which are highly cytotoxic and associated with the disease progression of autoimmune disorders.

A study by Abcuro showed that KLRG1 is the immune inhibitory receptor most closely associated with T-cell differentiation on a genome-wide scale. Compared to other clinical targets such as CTLA-4 and PD-1, which are active during the early and intermediate stages of T-cell differentiation, KLRG1 has the effect of completely disrupting the most differentiated and highly cytotoxic T-cells.

By precisely modulating cytotoxic T cells and NK cells, Abcuro is advancing two pipeline programs related to autoimmune diseases and rare cancers. The pipeline programs are ABC008 and ABC015, respectively.

ABC008 is Abcuro's lead product candidate. It is a first-in-class anti-KLRG1 antibody with high precision and efficacy.

On one hand, ABC008 can precisely target and eliminate the highly cytotoxic T cell populations and NK cells responsible for disease causation. At the same time, it preserves cells that do not express KLRG1, including naïve T cells and central memory T cells that enable the body to continue fighting infections, as well as regulatory T cells that protect against autoimmunity.

On the other hand, ABC008 acts as an "accelerator," capable of activating the anti-tumor activity of highly cytotoxic T cells and NK cells. This is because, in the cancer environment, effector T cells and NK cells are often suppressed by tumor cells expressing ligands that bind to the KLRG1 receptor. Therefore, the ability to selectively interrupt the interaction between KLRG1 on T cells and NK cells and immunosuppressive ligands expressed by cancer cells may activate the most mature, highly cytotoxic T cells and NK cells, thereby triggering their natural anti-tumor activity.

ABC008 aims to treat diseases mediated by highly cytotoxic T cells, including autoimmune muscle diseases such as inclusion body myositis (IBM), T-cell large granular lymphocyte leukemia (T-LGLL), and T-cell and NK-cell lymphomas. These cancers currently lack effective treatment options, and patients typically undergo surgery, radiotherapy, or receive potent cytotoxic drug treatments, but the prognosis is often poor.

Previously, Abcuro presented the Phase 1 clinical trial data of ABC008 IBM at GCOM 2022. The data showed that a dose-dependent depletion of highly cytotoxic KLRG1+ T cells was observed at three dose levels: 0.1 mg/kg (n=3), 0.5 mg/kg (n=3), and 2.0 mg/kg (n=5). Near-complete depletion of target cells (>95%) was observed at 28 days post-infusion at the two highest dose levels. The data demonstrated that ABC008 has favorable safety and efficacy, with no drug-related serious or severe adverse events, lymphopenia, or neutropenia observed.

At the same time, because high cytotoxic KLRG1+ T cells are present in many autoimmune diseases, Abcuro is further researching other indications for ABC008. Reportedly, its research team has linked KLRG1 to autoimmune diseases, including lupus erythematosus and rheumatoid arthritis.

ABC015 is another key pipeline of Abcuro. ABC015 is a KLRG1-blocking antibody candidate designed to block the binding of KLRG1 on mature T cells and NK cells with E- and N-cadherins on cancer cells, thereby enabling immune cells to more effectively kill cancer cells. Currently, ABC015 is in the preclinical development stage.

The market size of tumor immunotherapy will continue to expand. According to Frost & Sullivan analysis, the global tumor immunotherapy market size reached 42.6 billion US dollars in 2021. Driven by the increase in the number of new cancer cases, improved patient survival rates, extended treatment cycles, gradual improvement of policies and regulations, and the development of immunotherapy, it is expected to maintain rapid growth in the foreseeable future. By 2035, the global tumor immunotherapy market is projected to reach 311.2 billion US dollars, accounting for more than 48% of the total global oncology market.

Currently, CTLA-4, PD-1, and PD-L1 are the main immune checkpoints under research. According to data from the "2022 Global Tumor Immunotherapy Technology and Industry Research Report" released by DeepTech, as of March 2022, there are 19 monoclonal antibody drugs targeting PD-1, PD-L1, and CTLA-4 globally, with PD-1/PD-L1 accounting for about 90%, gradually forming a monopoly in these targets. However, issues such as low efficacy rates of single drugs, adverse side effects, and patients developing drug resistance still persist during their clinical use.

Discovering new targets and developing novel immune checkpoint inhibitor drugs is the path for newcomers in the cancer immunotherapy market. As a rising star in the immunotherapy market, it remains to be seen whether Abcuro can break the monopolistic pattern with ABC008.

References:

1. Co-inhibitory T cell receptor KLRG1: human cancer expression and efficacy of neutralization in murine cancer models.

2. Beyersdorf NB, Ding X, Karp K, Hanke T. Expression of inhibitory "killer cell lectin-like receptor G1" identifies unique subpopulations of effector and memory CD8T cells. Eur J Immunol. 2001; 31(12):3443-3452.

3. Henson SM, Akbar AN. KLRG1--more than a marker for T cell senescence. Age (Dordr). 2009;31(4):285-291. doi:10.1007/s11357-009-9100-9.