Multimeric Anti-DR5 IgM Agonist Antibody IGM-8444 Is a Potent Inducer of Cancer Cell Apoptosis and Synergizes with Chemotherapy and BCL-2 Inhibitor ABT-199

Abstract

Death receptor 5 (DR5) is an attractive target for cancer therapy due to its broad upregulated expression in multiple cancers and ability to directly induce apoptosis. Though anti-DR5 IgG antibodies have been evaluated in clinical trials, limited efficacy has been attributed to insufficient receptor crosslinking. IGM-8444 is an engineered, multivalent agonistic IgM antibody with 10 binding sites to DR5 that induces cancer cell apoptosis through efficient DR5 multimerization. IGM-8444 bound to DR5 with high avidity and was substantially more potent than an IgG with the same binding domains. IGM-8444 induced cytotoxicity in a broad panel of solid and hematologic cancer cell lines but did not kill primary human hepatocytes in vitro, a potential toxicity of DR5 agonists. In multiple xenograft tumor models, IGM-8444 monotherapy inhibited tumor growth, with strong and sustained tumor regression observed in a gastric PDX model. When combined with chemotherapy or the BCL-2 inhibitor ABT-199, IGM-8444 exhibited synergistic in vitro tumor cytotoxicity and enhanced in vivo efficacy, without augmenting in vitro hepatotoxicity. These results support the clinical development of IGM-8444 in solid and hematologic malignancies as a monotherapy and in combination with chemotherapy or BCL-2 inhibition.

Therapeutic targeting of TRAIL death receptors

“…Finally, IGM-8444 is an IgG DR5 antibody. With 10 binding units, it is capable of binding multiple receptors at once, facilitating receptor clustering [ 62 ]. IGM-8444 was found to induce apoptosis in a broad panel of solid and hematological malignancies [ 62 ].…”

“…With 10 binding units, it is capable of binding multiple receptors at once, facilitating receptor clustering [ 62 ]. IGM-8444 was found to induce apoptosis in a broad panel of solid and hematological malignancies [ 62 ]. A phase I study is currently recruiting patients to test IGM-8444 alone and in combination in subjects with cancer (NCT04553692).…”

Targeting regulated cell death pathways in acute myeloid leukemia

“…In particular, VDAC2 plays a role both in recruiting BAK to the MOM and in inhibiting its activation [17] . WEHI-9625 is a novel small molecule inducing BAK-mediated apoptosis in mice but is completely inactive against human BAK [87,88] . We found that ironomycin sequestered iron into lysosomes and subsequently reduced mitochondrial iron load, promoting the recruitment and non-canonical activation of BAX/BAK in AML in vitro and in vivo models.…”

“…Agonists of the TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4/5) have been tested in AML, but response rates are low [ 13 ] . Novel antibodies against TRAILR1 and TRAILR2 have shown promising preclinical data along with synergy with VEN and are currently tested in phase 1 [ Table 2 ] [ 89 ] . Eftozanermin alfa (ABBV-621), a second-generation TRAIL receptor agonist binding to the death-inducing DR4 and DR5 receptors, is currently being tested in solid tumors and hematological malignancies [ Table 2 ] [ 90 , 91 ] .…”

Antibody avidity and multi-specificity combined to confer protection against SARS-CoV-2 and resilience against viral escape

“…Among those, biologics assembled based on IgM 33 , synthetic nanocages 34 and Minibinder 35 formats have demonstrated superior neutralization properties against SARS-CoV-2 compared to conventional mAb formats. Additionally, the avid molecules GEN3009 35 , INBRX-106(Inhibrx) 36 and IGM-8444 37 are being tested in Phase I/II clinical trials for the treatment of hematological and solid tumors, highlighting the clinical benefit of multivalent antibody-presenting formats. Following a similar principle, but using the human light-chain apoferritin protomer to drive oligomerization of antibody fragments, we developed a platform called the Multabody (MB) to increase neutralization potency of antibodies targeting SARS-CoV-2 38 and HIV-1 39 .…”