CAT-8015: a second-generation pseudomonas exotoxin A-based immunotherapy targeting CD22-expressing hematologic malignancies.
OBJECTIVE
To compare the in vitro and in vivo efficacy of CAT-8015, a second-generation recombinant immunotoxin composed of disulfide-linked affinity matured V(H) and V(L) chains of the mouse anti-CD22 monoclonal antibody RFB4 fused to PE38, to the parental compound CAT-3888.


METHODS
The biological activity of CAT-8015 was examined in vitro using B-cell tumor lines and in vivo in a JD38-based s.c. tumor model in NCr athymic mice. Pharmacokinetics and interspecies scaling of CAT-8015 were evaluated in mice, rats, and cynomolgus monkeys. The potential toxicity of CAT-8015 was assessed in monkeys in a toxicologic study and compared with CAT-3888.


RESULTS
The IC50 values of CAT-8015 in vitro using the EHEB, MEC1, Daudi, CA46, and JD38 cell lines ranged from 0.3 to 8.6 ng/mL. Pharmacokinetic studies with CAT-8015 were conducted in mouse, rat, and cynomolgus monkey. The t1/2 was calculated to be 0.42, 0.61, and 0.79 hours and the Vss was 1.37, 5.57, and 140.3 mL in mouse, rat, and monkey, respectively. In vivo, when JD38 tumor-bearing animals were treated with CAT-8015 at doses > or =75 microg/kg at 48-hour intervals for a total of three doses, a rapid reduction in tumor volume and in some cases complete remission in tumor growth was observed. The comparative toxicologic study showed comparable clinical and anatomic pathology changes for CAT-8015 and CAT-3888.


CONCLUSIONS
CAT-8015 is a CD22-targeting immunotoxin that, in preclinical studies, has greatly improved efficacy compared with CAT-3888.
Alderson
Ralph F
RF
Cambridge Antibody Technology, Inc., Palo Alto, California, USA.
Kreitman
Robert J
RJ
Chen
Tianling
T
Yeung
Peter
P
Herbst
Ronald
R
Fox
Judy A
JA
Pastan
Ira
I
D036002:ADP Ribose Transferases / Q000627:therapeutic use*; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001427:Bacterial Toxins / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000628:therapy; D004768:Enterotoxins / Q000627:therapeutic use; D005098:Exotoxins / Q000627:therapeutic use*; D005260:Female; D000882:Haplorhini; D019337:Hematologic Neoplasms / Q000628:therapy*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity; D015448:Leukemia, B-Cell / Q000628:therapy; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D017207:Rats, Sprague-Dawley; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D037521:Virulence Factors / Q000627:therapeutic use*; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000906:Antibodies; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D004768:Enterotoxins; D005098:Exotoxins; D000922:Immunotoxins; D051918:Sialic Acid Binding Ig-like Lectin 2; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C431326:RFB4(dsFv)-PE38 recombinant immunotoxin; C541974:immunotoxin HA22