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Target Overview
CD20 is a transmembrane protein found on the surface of B cells including tumor B cells. CD20-targeting has been extensively pursued for the treatment of B cell associated malignancies including R/R DLBCL, FL, MCL and CLL.1-3 Bispecific CD20xCD3 antibodies demonstrated very high ORR and CR rates in the clinic1 and a number of monovalent and bivalent CD20xCD3 targeting engagers have been recently FDA approved for the treatment of R/R DLBCL and FL. However, current bispecific T cell engager treatments are associated with significant toxicity, including CRS and ICANS, limiting their therapeutic window and combination opportunities.
Compound Overview
AZD5492 is a first-in-class asymmetric, tri-specific monoclonal IgG1 antibody which harbors 2 Fab binding domains to human CD20, one VHH binding domain to human TCR, and one VHH binding domain to human CD8 co-receptor. The VHH domains allow preferential engagement of CD8+ T cells through CD8/TCR binding, inducing the formation of an artificial immunological synapse with CD20-positive target B cells thus leading to T-cell activation, release of cytolytic granzymes and perforin, and target B-cell killing. Compared to current CD20xCD3 clinical competitors which equally activate CD4 and CD8 T cells, AZD5492 CD8-biased targeting provides potent B cell killing efficacy while significantly reducing the risk of toxicity and associated cytokine release. The proposed indications for the clinical development of AZD5492 are R/R MCL, CLL/SLL, FL and LBCL.
Mechanism of Action
References
1. Kater AP, Eradat H, Niemann CU, et al. Presented at: 2023 International Workshop on CLL; October 6-9, 2023. Abstract 1546171. 2. Kater AP, Ye JC, Sandoval-Sus J, et al. Blood. 2022;140(suppl 1):850-851. 3. Jin S, Liu Y, Zhang Y, et al. Ther Adv Chronic Dis. 2023;14:20406223231215701.
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Abbreviations
CD20
cluster of differentiation 20
CD3
cluster of differentiation 3
CD8
cluster of differentiation 8
CLL
chronic lymphocytic leukemia
CR
complete remission
CRS
cytokine release syndrome
DLBCL
diffuse large B-cell lymphoma
Fc
fragment crystallizable region
FDA
Food & Drug Administration
FL
Follicular lymphoma
ICANS
immune effector cell-associated neurotoxicity syndrome
IgG1
immunoglobulin G1
LBCL
large B-cell lymphoma
MCL
mantle cell lymphoma
ORR
overall or objective response rate
R/R
relapsed/refractory
SLL
small lymphocytic lymphoma
TCR
T-cell receptor
VHH
variable domain of the heavy-chain
Target Overview
CD20 is a transmembrane protein found on the surface of B cells including tumor B cells. CD20-targeting has been extensively pursued for the treatment of B cell associated malignancies including R/R DLBCL, FL, MCL and CLL.1-3 Bispecific CD20xCD3 antibodies demonstrated very high ORR and CR rates in the clinic1 and a number of monovalent and bivalent CD20xCD3 targeting engagers have been recently FDA approved for the treatment of R/R DLBCL and FL. However, current bispecific T cell engager treatments are associated with significant toxicity, including CRS and ICANS, limiting their therapeutic window and combination opportunities.
Compound Overview
AZD5492 is a first-in-class asymmetric, tri-specific monoclonal IgG1 antibody which harbors 2 Fab binding domains to human CD20, one VHH binding domain to human TCR, and one VHH binding domain to human CD8 co-receptor. The VHH domains allow preferential engagement of CD8+ T cells through CD8/TCR binding, inducing the formation of an artificial immunological synapse with CD20-positive target B cells thus leading to T-cell activation, release of cytolytic granzymes and perforin, and target B-cell killing. Compared to current CD20xCD3 clinical competitors which equally activate CD4 and CD8 T cells, AZD5492 CD8-biased targeting provides potent B cell killing efficacy while significantly reducing the risk of toxicity and associated cytokine release. The proposed indications for the clinical development of AZD5492 are R/R MCL, CLL/SLL, FL and LBCL.
Mechanism of Action
References
1. Kater AP, Eradat H, Niemann CU, et al. Presented at: 2023 International Workshop on CLL; October 6-9, 2023. Abstract 1546171. 2. Kater AP, Ye JC, Sandoval-Sus J, et al. Blood. 2022;140(suppl 1):850-851. 3. Jin S, Liu Y, Zhang Y, et al. Ther Adv Chronic Dis. 2023;14:20406223231215701.
Clinical trial information
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Abbreviations
CD20
cluster of differentiation 20
CD3
cluster of differentiation 3
CD8
cluster of differentiation 8
CLL
chronic lymphocytic leukemia
CR
complete remission
CRS
cytokine release syndrome
DLBCL
diffuse large B-cell lymphoma
Fc
fragment crystallizable region
FDA
Food & Drug Administration
FL
Follicular lymphoma
ICANS
immune effector cell-associated neurotoxicity syndrome
IgG1
immunoglobulin G1
LBCL
large B-cell lymphoma
MCL
mantle cell lymphoma
ORR
overall or objective response rate
R/R
relapsed/refractory
SLL
small lymphocytic lymphoma
TCR
T-cell receptor
VHH
variable domain of the heavy-chain