Comparative In Vitro Evaluation of Anti-HIV Immunotoxin, Antibody-Drug Conjugate, and Radioimmunoconjugate Targeted by the Same Antibody
- Kuhlmann, Anne-Sophie
- Peters, Tami [ Montana State University: Chemistry & Biochemistry ]
- Hamlin, Donald K
- Li, Yawen
- Wang, Xinyi
- Stackhouse, Megan [ Montana State University: Chemistry & Biochemistry ]
- Cole, Frances M [ Montana State University: Chemistry & Biochemistry ]
- Martinez-Reyes, Jasmin
- Sandmaier, Brenda M
- Kiem, Hans-Peter
- Wilbur, D Scott
- Harrington, Robert D
- Pincus, Seth H [ Montana State University: Chemistry & Biochemistry ]
BACKGROUND: We are developing cytotoxic immunoconjugates (CICs) to eliminate HIV-infected cells. We investigated the efficacy and kinetics of killing by different forms of CICs targeted by the same monoclonal antibody (mAb), an immunotoxin (IT), antibody-drug conjugate (ADC), and radioimmunoconjugate (RIC). METHODS: We compared in vitro effects of CICs made by conjugating anti-gp41 mAb 7B2 to deglycosylated ricin A chain (7B2-dgA), the anthracycline derivative PNU-159682 (7B2-PNU), or the alpha-emitting isotope actinium-225 (7B2-225Ac). Kinetic analyses of cell growth were performed measuring electrical impedance every 15 min over a 7-day period using cells stably expressing the HIV envelope and Env-negative parent cells. RESULTS: 7B2-dgA and 7B2-225Ac were more potent and acted more rapidly to kill cells than 7B2-PNU. Both the 7B2-PNU and 7B2-225Ac induced bystander-cell killing, whereas the IT did not and consequently allowed the outgrowth of Env-negative cells. Low dose or brief exposure to 7B2-PNU resulted in an increased rate of cell growth. CONCLUSIONS: An IT, ADC, and RIC showed substantial differences in the degree of specific toxicity, kinetics, and mechanisms of killing. The results of this side-by side comparison have implications for the development of CICs to treat HIV, as well as other conditions.