Phase I study of anticolon cancer humanized antibody A33.
OBJECTIVE
Humanized A33 (huA33; IgG1) monoclonal antibody detects a determinant expressed by 95% of colorectal cancers and can activate immune cytolytic mechanisms. The present study was designed to (a) define the toxicities and maximum tolerated dose of huA33 and (b) determine huA33 immunogenicity.


METHODS
Patients (n = 11) with advanced chemotherapy-resistant colorectal cancer received 4-week cycles of huA33 at 10, 25, or 50 mg/m(2)/week. Serum samples were analyzed using biosensor technology for evidence of human antihuman antibody (HAHA) response.


RESULTS
Eight of 11 patients developed a HAHA response. Significant toxicity was limited to four patients who developed high HAHA titers. In two of these cases, infusion-related reactions such as fevers, rigors, facial flushing, and changes in blood pressure were observed, whereas in the other two cases, toxicity consisted of skin rash, fever, or myalgia. Of three patients who remained HAHA negative, one achieved a radiographic partial response, with reduction of serum carcinoembryonic antigen from 80 to 3 ng/ml. Four patients had radiographic evidence of stable disease (2, 4, 6, and 12 months), with significant reductions (>25%) in serum carcinoembryonic antigen levels in two cases.


CONCLUSIONS
The complementarity-determining region-grafted huA33 antibody is immunogenic in the majority of colon cancer patients (73%). HAHA activity can be measured reproducibly and quantitatively by BIACORE analysis. Whereas the huA33 construct tested here may be too immunogenic for further clinical development, the antitumor effects observed in the absence of antibody-mediated toxicity and in this heavily pretreated patient population warrant clinical testing of other IgG1 humanized versions of A33 antibody.
Welt
Sydney
S
Department of Medicine at Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. welts@mskcc.org
Ritter
Gerd
G
Williams
Clarence
C
Cohen
Leonard S
LS
John
Mary
M
Jungbluth
Achim
A
Richards
Elizabeth A
EA
Old
Lloyd J
LJ
Kemeny
Nancy E
NE
D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008875:Middle Aged; D013997:Time Factors; D014057:Tomography, X-Ray Computed
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C104258:GPA33 protein, human; C504395:Gpa33 protein, mouse; D008562:Membrane Glycoproteins