Toxicity-reducing potential of extracorporeal affinity adsorption treatment in combination with the auristatin-conjugated monoclonal antibody BR96 in a syngeneic rat tumor model.
BACKGROUND
Antibody-drug conjugates, comprising monoclonal antibodies (MoAbs) that bind to tumor-associated antigens, display different toxicity profiles compared with radiolabeled MoAbs. Dose-limiting toxicities may include damage to the liver and myelotoxicity. The drug component is the antimitotic agent auristatin, which is 100-1000 times more potent than doxorubicin. Consequently, auristatin antibody-drug conjugates require a high selectivity in tumor targeting to display pronounced activity at well-tolerated doses. We have evaluated the possibility of increasing the therapeutic index of BR96-auristatin by combining the administration of conjugates with subsequent extracorporeal affinity adsorption treatment.


METHODS
Rats were injected with biotinylated, monomethyl auristatin F (MMAF)-conjugated monoclonal antibody BR96. The conjugate was then removed from the circulation by extracorporeal affinity adsorption treatment, 24 hours postinjection using an avidin affinity column. By analyzing blood parameters for 100 days, myelotoxicity, hepatotoxicity, and nephrotoxicity were assessed. Body weight, general status, and tumor size were also recorded. The toxicity-reducing effect of extracorporeal affinity adsorption treatment was evaluated.


RESULTS
Extracorporeal affinity adsorption treatment removed 85%-90% of BR96-MMAF from the circulation. Early toxicity-related death was seen in nontumor-bearing animals that were given MMAF-conjugated BR96, in contrast to animals that were given a higher amount of BR96-MMAF with subsequent extracorporeal affinity adsorption treatment, in which all survived 100 days postinjection. Extracorporeal affinity adsorption treatment reduced the loss of body weight, myelotoxicity, and hepatotoxicity.


CONCLUSIONS
Extracorporeal affinity adsorption treatment can be used to reduce the toxicity associated with administration of BR96-MMAF conjugates, making it possible to increase the amount of conjugates administered. The combined treatment will be further optimized in future studies.
Nilsson
Rune
R
Department of Oncology, Lund University, Lund, Sweden. rune.nilsson@med.lu.se
Mårtensson
Linda
L
Eriksson
Sophie E
SE
Sjögren
Hans-Olov
HO
Tennvall
Jan
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D005112:Extracorporeal Circulation; D005240:Feasibility Studies; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D011914:Rats, Inbred BN; D015431:Weight Loss
D000911:Antibodies, Monoclonal; C507851:BR96 monoclonal antibody; D018796:Immunoconjugates; D009842:Oligopeptides; C495575:monomethyl auristatin E