PMID- 33930269
OWN - NLM
STAT- MEDLINE
DCOM- 20211112
LR  - 20211112
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Linking)
VI  - 60
IP  - 19
DP  - 2021 May 18
TI  - Covalent Stabilization of Antibody Recruitment Enhances Immune Recognition of 
      Cancer Targets.
PG  - 1447-1458
LID - 10.1021/acs.biochem.1c00127 [doi]
AB  - Antibody recruiting molecules (ARMs) represent an important class of 
      "proximity-inducing" chemical tools with therapeutic potential. ARMs function by 
      simultaneously binding to a hapten-specific serum antibody (Ab) (e.g., 
      anti-dinitrophenyl (DNP)) and a cancer cell surface protein, enforcing their 
      proximity. ARM anticancer efficacy depends on the formation of ARM:Ab complexes 
      on the cancer cell surface, which activate immune cell recognition and 
      elimination of the cancer cell. Problematically, ARM function in human patients 
      may be limited by conditions that drive the dissociation of ARM:Ab complexes, 
      namely, intrinsically low binding affinity and/or low concentrations of 
      anti-hapten antibodies in human serum. To address this potential limitation, we 
      previously developed a covalent ARM (cARM) chemical tool that eliminates the 
      ARM:antibody equilibrium through a covalent linkage. In the current study, we set 
      out to determine to what extent maximizing the stability of ARM:antibody 
      complexes via cARMs enhances target immune recognition. We observe cARMs 
      significantly increase target immune recognition relative to ARMs across a range 
      of therapeutically relevant antibody concentrations. These results demonstrate 
      that ARM therapeutic function can be dramatically enhanced by increasing the 
      kinetic stability of ARM:antibody complexes localized on cancer cells. Our 
      findings suggest that a) high titres/concentrations of target antibody in human 
      serum are not neccessary and b) saturative antibody recruitment to cancer cells 
      not sufficient, to achieve maximal ARM therapeutic function.
FAU - Kapcan, Eden
AU  - Kapcan E
FAU - Lake, Benjamin
AU  - Lake B
FAU - Yang, Zi
AU  - Yang Z
FAU - Zhang, Ali
AU  - Zhang A
FAU - Miller, Matthew S
AU  - Miller MS
FAU - Rullo, Anthony F
AU  - Rullo AF
AUID- ORCID: 0000-0002-5868-3583
LA  - eng
GR  - CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210430
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Antibodies)
RN  - 0 (Haptens)
RN  - 0 (Immunoglobulins)
RN  - 0 (immunoglobulin B)
SB  - IM
MH  - Antibodies/*chemistry/therapeutic use
MH  - Antibody Formation
MH  - Haptens/chemistry/immunology
MH  - Humans
MH  - Immunoglobulins
MH  - Immunotherapy/*methods
MH  - Kinetics
MH  - Neoplasms/drug therapy/*immunology
MH  - Protein Binding/immunology
EDAT- 2021/05/01 06:00
MHDA- 2021/11/16 06:00
CRDT- 2021/04/30 20:10
PHST- 2021/05/01 06:00 [pubmed]
PHST- 2021/11/16 06:00 [medline]
PHST- 2021/04/30 20:10 [entrez]
AID - 10.1021/acs.biochem.1c00127 [doi]
PST - ppublish
SO  - Biochemistry. 2021 May 18;60(19):1447-1458. doi: 10.1021/acs.biochem.1c00127. 
      Epub 2021 Apr 30.