Antibody responses to macrocycles in lymphoma.
Metallic radioimmunoconjugates have promise for radioimmunoimaging and therapy. Macrocyclic chelating agents allow formation of stable metallic radioimmunoconjugates but have been reported to be immunogenic. This study assesses human antibody responses in patients that were imaged or treated with radiolabeled Lym-1 containing the macrocyclic chelators 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA) or 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA).


METHODS
One to six doses (median 1) and 6 to 285 mg (median 33) 67Cu-2IT-BAT (2-iminothiolane bromoacetamidobenzyl TETA)- or 111In-2IT-BAD (2-iminothiolane bromoacetamidobenzyl DOTA)-Lym-1 were administered to each of 18 patients with lymphocytic malignancies. Solid-phase ELISA, utilizing unchelated Lym-1 or human serum albumin conjugated to DOTA, TETA or 2IT-bromoacetamidobenzyl-ethylenediaminetetraacetic acid (BABE) as coating antigens, was used to characterize antibody responses against 67Cu-2IT-BAT-Lym-1 and 111In-2IT-BAD-Lym-1 by quantitating antibodies against the Lym-1, DOTA, TETA or 2IT moieties, respectively.


RESULTS
None of the patients had evidence for serum sickness. No patient that received 111In-2IT-BAD-Lym-1 developed antibodies to Lym-1 or DOTA. Two (15%) of the 13 patients that received 67Cu-2IT-BAT-Lym-1 developed antibodies against both TETA and Lym-1, and an additional patient developed antibodies against Lym-1 only. No patient developed an antibody response solely against the macrocycle, nor did any of the patients generate antibodies against the 2IT molecule. HAMA levels were many times greater in amount than HATA levels even when their relative molecular masses were considered.


CONCLUSIONS
Although macrocycles such as DOTA and TETA, and other chelates, can be haptens and thus potentially immunogenic, our findings do not support the view that macrocycles are more immunogenic than other radiometal chelating agents.
DeNardo
G L
GL
Department of Internal Medicine, University of California Davis Medical Center, Sacramento, USA.
Mirick
G R
GR
Kroger
L A
LA
O'Donnell
R T
RT
Meares
C F
CF
DeNardo
S J
SJ
D000818:Animals; D000917:Antibody Formation; D003301:Copper Radioisotopes / Q000627:therapeutic use; D004492:Edetic Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D006571:Heterocyclic Compounds / Q000276:immunology* / Q000627:therapeutic use; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology*; D007074:Immunoglobulin G / Q000032:analysis / Q000096:biosynthesis*; D007205:Indium Radioisotopes / Q000627:therapeutic use; D008228:Lymphoma, Non-Hodgkin / Q000000981:diagnostic imaging / Q000276:immunology* / Q000532:radiotherapy; D008297:Male; D051379:Mice / Q000276:immunology; D008875:Middle Aged; D016719:Radioimmunodetection; D016499:Radioimmunotherapy
D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D004492:Edetic Acid