GenFleet Therapeutics, a commercial-stage biopharmaceutical company focusing on cutting-edge therapies in oncology and immunology, today announced the preclinical findings of GFS202A, a clinical-stage antagonistic GDF15/ID-L6 bispecfic antibody, at the poster presentation of the 2025 American Association for Cancer Research (AACR) Annual Meeting.
GFS202A is the world’s first clinical-stage GDF15/IL-6 bispecific antibody for cachexia, as well as the first China-developed GDF15-targeted therapy entering clinical development. Preclinical research demonstrated its high-affinity, specific binding to human GDF15 and IL-6 along with potent inhibition of their downstream signaling pathways. Studies of tumor-induced cachectic models demonstrated the reversal of weight loss by GFS202A at low effective dosages, producing dose-dependent increases in body weight, lean body mass and adipose tissue while suppressing inflammatory responses effectively. Furthermore, primate toxicology studies displayed favorable safety/tolerability and pharmacokinetic properties of GFS202A. With the phase I trial for cancer cachexia ongoing in China, GFS202A also holds vast potential for treating cachectic conditions associated with chronic diseases such as heart failure, COPD, chronic nephritis, positioning it for a broad therapeutic market.
"This annual meeting featured abstracts from over 100 Chinese biopharma innovators, establishing them as essential contributors to the global research dialogue. The conference spotlighted RAS-targeting therapies as one of the focal points in small-molecule development, while participation of bispecific/multispecific antibody programs was also on the rise. Preclinical data of our company's assets were selected for poster presentation at this event, spanning the findings of selective and pan-RAS inhibitors, alongside our first bispecific antibody entering clinical stage. Breakthroughs in these programs reflect the strategic depth of our RAS therapeutic portfolio and exemplify our vision to tackle broad indications through innovative molecular modalities. Leveraging our proven expertise, we are projected to deliver more life-saving treatments to integrate validated mechanisms with leading-edge innovation. " stated Fusheng Zhou, Ph.D., Vice President of our GenFleet’s Drug Discovery Department.
GFS202A: a novel GDF15×IL-6 bispecific antibody for the treatment of cachexia（Abstract No.：6078）
Potent inhibition of GDF15/IL-6 ligand-receptor interaction and downstream signaling
GDF15 and IL-6 have been identified as important cytokines associated with cachexia symptoms, therapeutic choices and poor prognosis. GDF15 is a key factor in cell growth, differentiation, and metabolic stress responses; its overexpression is common in pathological conditions such as cancer, heart or kidney failure, and metabolic diseases. IL-6 is involved in regulating immune responses and cell differentiation, and its expression levels are significantly elevated in various chronic inflammatory and autoimmune diseases. In vitro experiments showed the binding of GFS202A with high affinity and specificity to human GDF15 and IL-6 proteins, in TGF-β and IL-6 families respectively. It demonstrated potent blocking of the interaction between GDF15 and its receptor GFRAL, as well as the inhibition of GDF15/GFRAL/RET signaling pathway. Additionally, it strongly blocks the interaction between IL-6 and its receptor, as well as the IL-6/IL-6R/gp130 signaling pathway.
Low-dose reversal of weight loss and superior reduction in C-reactive protein versus benchmark GDF15 antibody
Cachexia manifests through progressive weight loss, lean body mass depletion, and adipose tissue reduction. In tumor-bearing murine models administered with single or multiple administrations within 20-40 days, GFS202A exhibited to initiate improvements in body weight, lean mass, adipose tissue dose-dependently, and reduce C-reactive protein (CRP) levels.
Comparative analysis demonstrated similar efficacy between GFS202A and poncegromab (a GDF15 antibody) in restoring body weight, muscle, and fat mass at equimolar doses. Notably, GFS202A exhibited greater CRP reduction at lower dosage than poncegromab, highlighting GFS202A's enhanced anti-inflammatory potential. Additionally, a 4-week pharmacokinetic & toxicology study of cynomolgus monkeys indicated GFS202A was well tolerated and exhibited favorable PK characteristics：no adverse effects on cardiovascular, respiratory and central nervous system functions were observed in the study.
Cachexia represents a multifaceted metabolic disorder with profound clinical consequences, impairing treatment outcomes and overall survival. Cancer is one of the major causes of cachexia, with an incidence rate exceeding 50% in several tumor types and a mortality rate of up to 30%. GFS202A has become the first cachexia-targeted therapy in China to enter clinical trial. Presently, neither FDA nor NMPA has approved any cachexia-specific treatments, underscoring the urgent medical needs across oncology and chronic disease tr
About GDF 15，IL-6 and GFS202A
GDF15 (Growth Differentiation Factor-15) is a member of the TGF-β (Transforming Growth Factor-beta) superfamily of proteins, while the glial cell-derived neurotrophic factor receptor alpha (GFRAL) is the specific receptor for GDF-15. GDF15 acts on receptor GFRAL and co-receptor RET which are expressed on neurons localized in area postrema (AP) and nucleus of the solitary tract (NTS) of the hindbrain, subsequently triggers downstream signal. Numerous studies have indicated that the level of GDF-15 is significantly elevated in cancer patients. GDF-15 can activate downstream signaling pathways, thereby promoting growth, migration, and proliferation of cancer cells. Additionally, it inhibits DC (dendritic cell)-mediated T-cell stimulation and the activation and infiltration of cytotoxic T cells.IL-6 can enter the central nervous system and, through the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, induce atrophy in peripheral tissues such as muscle. It can also act peripherally by activating the JAK/STAT and MAPK signaling pathways, inducing apoptosis in skeletal muscle cells and the breakdown of adipose tissue. Persistent high levels of IL-6 are strongly associated with shorter survival.In preclinical research of GFS202A (a GDF15/IL-6 bispecific antibody), the body weight, adipose tissue and muscle mass increase dose-dependently in animal models; notably, GFS202A effectively reduces C-reactive protein levels and alleviates inflammatory responses. GFS202A also demonstrated favorable safety/tolerability profile in preclinical animal studies.
About Cachexia
Cachexia is a complex disease characterized by debilitating symptoms including disrupted metabolic regulation, significant weight loss, and progressive muscle breakdown. It is commonly observed in chronic conditions such as cancer, chronic obstructive pulmonary disease (COPD), and chronic nephritis. Cancer cachexia is a continuum with three stages of clinical relevance and not all patients traverse the entire spectrum. In precachexia, early clinical and metabolic signs can precede involuntary weight loss. The cachexia stage is marked by significant weight loss, an obvious decrease in skeletal muscle index, reduced food intake, and systemic inflammation. Refractory cachexia is associated with active catabolism, or the presence of factors that render active management of weight-loss no longer possible or appropriate; at this stage, the cachexia can be clinically refractory because of very advanced cancer or the presence of rapidly progressive cancer unresponsive to anticancer therapy. In China, no targeted therapies have been approved for cancer cachexia. In clinical practice, nutritional support and hormonal medications are commonly used to maintain the appetite and body weight of patients with advanced cancer.
