PMID- 34711645
OWN - NLM
STAT- MEDLINE
DCOM- 20220325
LR  - 20231006
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 20
IP  - 12
DP  - 2021 Dec
TI  - 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.
PG  - 2483-2494
LID - 10.1158/1535-7163.MCT-20-1132 [doi]
AB  - 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.
CI  - (c)2021 The Authors; Published by the American Association for Cancer Research.
FAU - Wang, Beatrice T
AU  - Wang BT
AUID- ORCID: 0000-0002-5857-8097
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Kothambawala, Tasnim
AU  - Kothambawala T
AUID- ORCID: 0000-0001-8865-4241
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Wang, Ling
AU  - Wang L
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Matthew, Thomas J
AU  - Matthew TJ
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Calhoun, Susan E
AU  - Calhoun SE
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Saini, Avneesh K
AU  - Saini AK
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Kotturi, Maya F
AU  - Kotturi MF
AUID- ORCID: 0000-0002-9387-860X
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Hernandez, Genevive
AU  - Hernandez G
AUID- ORCID: 0000-0001-9226-1889
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Humke, Eric W
AU  - Humke EW
AUID- ORCID: 0000-0002-1137-8557
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Peterson, Marvin S
AU  - Peterson MS
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Sinclair, Angus M
AU  - Sinclair AM
AUID- ORCID: 0000-0002-2467-3301
AD  - IGM Biosciences Inc., Mountain View, California.
FAU - Keyt, Bruce A
AU  - Keyt BA
AD  - IGM Biosciences Inc., Mountain View, California. bkeyt@igmbio.com.
LA  - eng
PT  - Journal Article
DEP - 20211028
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Immunoglobulin M)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Sulfonamides)
RN  - N54AIC43PW (venetoclax)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Apoptosis
MH  - Bridged Bicyclo Compounds, Heterocyclic/pharmacology/*therapeutic use
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Female
MH  - Genes, bcl-2/*genetics
MH  - Humans
MH  - Immunoglobulin M/pharmacology/*therapeutic use
MH  - Mice
MH  - Mice, Nude
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*antagonists & inhibitors
MH  - Sulfonamides/pharmacology/*therapeutic use
PMC - PMC9398157
EDAT- 2021/10/30 06:00
MHDA- 2022/03/26 06:00
PMCR- 2022/08/23
CRDT- 2021/10/29 05:49
PHST- 2020/12/31 00:00 [received]
PHST- 2021/07/07 00:00 [revised]
PHST- 2021/09/15 00:00 [accepted]
PHST- 2021/10/30 06:00 [pubmed]
PHST- 2022/03/26 06:00 [medline]
PHST- 2021/10/29 05:49 [entrez]
PHST- 2022/08/23 00:00 [pmc-release]
AID - 1535-7163.MCT-20-1132 [pii]
AID - MCT-20-1132 [pii]
AID - 10.1158/1535-7163.MCT-20-1132 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2021 Dec;20(12):2483-2494. doi: 10.1158/1535-7163.MCT-20-1132. 
      Epub 2021 Oct 28.