Abstract 6078: GFS202A, a novel GDF15×IL-6 bispecific antibody for the treatment of cachexia

Abstract Cancer cachexia is a complicated syndrome characterized by loss of body mass, anorexia and progressive functional impairment. It is associated with intolerance and poor response to therapy, reduced life quality and unfavourable prognosis. Currently, pharmacologic intervention is limited without any FDA approved drugs. GDF15 and IL-6 derived from tumor and immune cells are major drivers of cachexia. 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. IL-6 initiates trans- and classic- signals upon binding to soluble and membrane IL-6Rα respectively. These pathways together regulate adipose catabolism, muscle proteolysis, and impact appetite through neuronal circuit. GFS202A is a humanized tetravalent GDF15×IL-6 bispecific antibody, the Fc region is engineered to reduce Fc-mediated immune effect. It had high affinity to human GDF15 (KD 0.05 nM) and IL-6 (KD 0.313 nM), cross-reacted with cynomolgus monkey counterparts. GFS202A bound to antigens with high specificity, without binding to TGFβ family members GDF-8, BMP-3 and TGFβ1 or other IL-6 family members. GFS202A blocked interaction between GDF15 and GFRAL (IC50 2.653 nM), neutralized GDF15-induced GFRAL/RET signal activation in 293T-luc reporter cells (IC50 0.242 nM). GFS202A can inhibit both trans- and classic IL-6 signal in IL-6-induced BaF3-gp130 and BaF3-IL-6Rα/gp130 cells (IC50 1.967 nM and 2.734 nM). In vivo efficacy was evaluated in tumor-induced cachexia mice. In human fibrosarcoma HT-1080 induced cachectic model, weekly IV administration of GFS202A effectively reversed body weight loss, 1, 4, 12 mg/kg GFS202A resulted in 5.61%, 11.61% and 24.71% tumor-free body weight gain when compared to isotype control. In ovarian cancer TOV21G cachectic model, weekly treatment of 1, 4, 12 mg/kg GFS202A increased tumor-free body weight by 4.55%, 20.62% and 37.35% respectively compared to isotype control. Adipose and muscle tissue weights in GFS202A groups also increased dose-dependently. Noticeably, GFS202A effectively reversed CRP elevation, indicating the function of bispecific antibody in relieving inflammation. In cynomolgus monkey PK study, single dose of GFS202A exhibited linear PK profile, Cmax and AUC increased in proportion with dose at the range of 1∼25 mg/kg. GFS202A was well tolerated in cynomolgus monkey toxicity study, with a weekly dose regimen (qw ×5) the NOAEL was 300 mg/kg. Taking together, these preclinical findings show the potential of GFS202A as an innovative treatment for cachexia, with a projected clinical trial initiation in the first half of 2025. Citation Format: Xiangyu He, Jingyang Zhang, Yumei Li, Hongcan Ren, Siyuan Le, Fusheng Zhou, Jiong Lan, Qiang Lu. GFS202A, a novel GDF15×IL-6 bispecific antibody for the treatment of cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6078.