Anti-CD22-MCC-DM1: an antibody-drug conjugate with a stable linker for the treatment of non-Hodgkin's lymphoma.
Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL.
Polson
A G
AG
Research and Early Development, Genentech, South San Francisco, CA 94080, USA. polson@gene.com
Williams
M
M
Gray
A M
AM
Fuji
R N
RN
Poon
K A
KA
McBride
J
J
Raab
H
H
Januario
T
T
Go
M
M
Lau
J
J
Yu
S-F
SF
Du
C
C
Fuh
F
F
Tan
C
C
Wu
Y
Y
Liang
W-C
WC
Prabhu
S
S
Stephan
J-P
JP
Hongo
J-A
JA
Dere
R C
RC
Deng
R
R
Cullen
M
M
de Tute
R
R
Bennett
F
F
Rawstron
A
A
Jack
A
A
Ebens
A
A
D000818:Animals; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy*; D008252:Macaca fascicularis; D009368:Neoplasm Transplantation; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*
D018796:Immunoconjugates; D051918:Sialic Acid Binding Ig-like Lectin 2