College Papers

Overexpressing MAb, 1C1 over a non-cleavable linker maleimidocaproyl

Overexpressing EphA2 receptor in various cancer tissues and
limited expression or absent in normal adult tissues is promising an attractive
target for the development of ongoing immunoconjugate therapy. Lee et al
examined monomethyl auristatin phenylalanine (MMAF), a chemotherapeutic agent
to conjugate with anti-EphA2 MAb, 1C1 over a non-cleavable linker
maleimidocaproyl (mc), 1C1-mcMMAF was examined for its anti-tumor efficacy in
the EphA2+ ovarian derive Hey 8 cells and orthotopic ovarian cancer models.
Treatment with 1C1-mcMMAF in vitro decreased HeyA8 cells viability and in vivo
inhibit tumor growth via reduced cell proliferation and increased apoptosis in
an EphA2-specific manner (137) Another study reported that 1C1-mcMMAF(product
name MEDI-547) inhibited EphA2 expression in endometrial cancer derived HEC1A
and Ishikawa cells by decreasing cell viability and promoting apoptosis(138). Phase-I
open-label study of 1C1-mcMMAF reported that treatment with the 1C1-mcMMAF
patient’s was rejected in the safety issues particularly uncontrolled bleeding
and coagulation events(139). Successively, encouraging events in rodents were
obtained by conjugating the 1c1 antibody with the microtubule inhibitor
auristatin to deliver the cytotoxic agent to EphA2+ tumors. Unfortunately, a
Phase I clinical trial was terminated owing to treatment-related bleeding and
clotting issues(139). An EphrinA1-PE38 a novel, specific recombinant
immunotoxin yielded in hMSCs through adenoviral transduction and EphrinA1-PE38
carrying hMSCs inhibited  EphA2
overexpressing GBM cells in vitro and in vivo reduced the glioblastoma
growth(141). Recently, microPET used to characterized EphA2 MABs to improve
antibody dependent conjugation (ADC) system for better tumor targets and
decreased the side-effects of anti-EphA2 targeting therapy(142).
Furthermore,  glycol-engineering  approach is used to site-specific monoclonal
EphA2, 1C1 conjugated with pyrrolo benzenzodia zeprin alter the pharmacokinetic
properties of ADC proteins and highly effective to killed EphA2 positive PC3
cells(144)