Background
Cancer-associated cachexia is a metabolic wasting syndrome driven by tumor-secreted factors, where growth differentiation factor 15 (GDF-15) plays a critical role in inducing anorexia and tissue loss. Additionally, vascular endothelial growth factor A (VEGFA) drives tumor angiogenesis and progression. Given that radiation and chemotherapy frequently induce GDF-15 release—exacerbating cachexia—while VEGFA inhibitors are standard clinical partners, simultaneously targeting both pathways represents a promising therapeutic strategy. BCG051 was developed as a first-in-class, fully human IgG1K (LALA) bispecific antibody designed to inhibit tumor progression and reverse cachexia concurrently.
Methods
In vitro binding affinity and dual-target kinetics were determined using surface plasmon resonance (SPR) and blocking assays. Physicochemical stability was evaluated via stress tests. In vivo anti-tumor efficacy and cachexia mitigation were investigated across multiple mouse models, including MKN45 gastric and LS513 colorectal CDX models, alongside NSCLC and PDAC patient-derived xenografts (PDX). Pharmacokinetics (PK) were characterized across humanized mouse strains.
Results
In vitro, BCG051 demonstrated picomolar affinity to GDF-15 and VEGFA across species, yielding superior VEGFA/VEGFR2 pathway blockade compared to bevacizumab. The molecule maintained high purity and structural integrity under thermal, alkaline, and acidic stress. In vivo, BCG051 achieved robust, superior tumor growth inhibition compared to bevacizumab across gastric, colorectal, NSCLC, and PDAC models. Crucially, it significantly reversed weight loss, preserved lean mass and adipose tissue, and prolonged survival—metabolic benefits absent in anti-VEGF monotherapy. BCG051 regulated body weight independently of tumor shrinkage and exhibited strong synergy with cisplatin or anti-PD-I therapies while mitigating chemotherapy-induced weight loss. Its PK profile was favorable and comparable to clinical benchmarks.
Conclusions
BCG051 successfully combines high-affinity GDF-15 and VEGFA inhibition into a single agent, delivering potent anti-tumor synergy and robust cachexia reversal in preclinical models. Coupled with favorable developability and pharmacokinetics, these dual actions support the clinical advancement of BCG051 for advanced cancer patients with metabolic wasting
