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Effectiveness of Antibody-Drug Conjugate (ADC): Results of In Vitro and In Vivo Studies.

ABSTRACT: BACKGROUND Human lung cancer is still the leading cause of cancer-related mortality around the world, although a variety of new therapies have been used in the treatment of this disease. Antibody-drug conjugate (ADC) has revolutionized the field of cancer therapy in recent decades. Unlike traditional chemotherapy that damages the healthy cells, ADC first utilizes monoclonal antibodies to bind tumor-specific antigen targets and then deliver a highly potent cytotoxic agent to kill tumor cells. Thus, ADC can benefit cancer patients because this drug has less severe adverse effects. MATERIAL AND METHODS One type of ADC for non-small cell lung cancer (NSCLC) was designed in this study: Erbitux-vc-PAB-MMAE. It is a mouse/human chimeric monoclonal antibody, Erbitux, conjugating to the tubulin inhibitor auristatin. The efficacy of ADC was investigated through in vitro and in vivo studies. RESULTS Our in vitro study demonstrated that Erbitux-vc-PAB-MMAE could effectively inhibit proliferation of human lung cancer A549 cells, and arrested cell cycle at G2/M phase. In a mouse xenograft model, the results indicated that Erbitux-vc-PAB-MMAE could be exactly delivered to tumor tissues, and effectively inhibited tumor growth via promoting apoptosis of cancer cells. CONCLUSIONS The antibody portion of an ADC drug (Erbitux) was used as a vector to bring the effector molecule (tubulin inhibitor MMAE) to the targeted tumor tissue. This antibody-drug conjugate can exert a strong anti-tumor effect.

SUBMITTER: Kang X

PROVIDER: S-EPMC5855927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An increasing number of monoclonal antibodies and derivatives such as antibody-drug conjugates (ADC) are of the IgG1 and IgG4 isotype with distinct structural and functional properties. In cases where antibody-mediated cytotoxicity is not desired, IgG4 is often used, as its Fc region is relatively poor at inducing antibody-dependent cell-mediated or complement-dependent cytotoxicity. IgG4 ADCs with highly cytotoxic drugs against proliferating target cells but which lack or have diminished antibody effector functions against quiescent cells may have a favorable safety profile compared to IgG1. Another unique property of the IgG4 subclass is the capability to exchange half antibodies in vivo creating randomly bispecific antibodies. To investigate the functional properties of process-derived antibody species, and determine the influence of shuffling on the therapeutic efficacy, several model antibodies on the basis of the anti-CD138 antibody-drug conjugate BT062 (Indatuximab ravtansine) were generated: (I) A wild type nBT062, (II) a stable nBT062 comprising mutations to prevent half-antibody exchange, (III) a half nBT062 lacking covalent binding between two heavy chains and (IV) a stabilized, bispecific nBT062-natalizumab antibody with a second, monovalent specificity against CD49d. All nBT062 model variants were capable of CD138-specific binding and antigen-mediated internalization into cells. Furthermore, all nBT062 models inhibited tumor growth in vitro after conjugation with the maytansinoid DM4. The in vivo effects of the different molecular variants were assessed in the MAXF1322 xenograft model. The bispecific nBT062-natalizumab-DM4 demonstrated the least efficacy and was only moderately active even without the co-administration of a human IgG preparation. Wild type, stable and half nBT062-DM4 models demonstrated great anti-tumor activities. The efficacy of wild type and half nBT062-DM4 was reduced in the presence of IgG, while stable nBT062-DM4 was only marginally influenced. These pre-clinical data demonstrate the advantage of introducing half-antibody exchange-preventing mutations into therapeutic IgG4-based antibody drug-conjugates.

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Effectiveness of Antibody-Drug Conjugate (ADC): Results of In Vitro and In Vivo Studies.

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