<p>ABBV-399, a c-Met Antibody Drug Conjugate that Targets Both MET Amplified and c-Met Overexpressing Tumors, Irrespective of MET Pathway Dependence. Figure S1 shows ABBV-399 is internalized upon binding to tumor cells. Figure S2 shows the down-regulation of phospho- and total c-Met and downstream signaling molecules upon treatment with ABBV-399</p>
Abstract Antibody–drug conjugates (ADC) have emerged as one of the pillars of clinical disease management in oncology. The biggest hurdle to widespread development and application of ADCs has been a narrow therapeutic index. Advances in antibody technologies and formats as well as novel linker and payload chemistries have begun to facilitate structural improvements to ADCs. However, the interplay of structural characteristics with physiologic and pharmacologic factors determining therapeutic success has garnered less attention. This review elaborates on the pharmacology of ADCs, the pathophysiology of cancerous tissues, and the reciprocal consequences on ADC properties and functions. While most currently approved ADCs utilize either microtubule inhibition or DNA damage as primary mechanisms of action, we present arguments to expand this repertoire and highlight the need for payload mechanisms that exploit disease-specific vulnerabilities. We promote the idea that the choice of antibody format, targeting antigen, linker properties, and payload of an ADC should be deliberately fit for purpose by taking the pathophysiology of disease and the specific pharmacology of the drug entity into account, thus allowing a higher probability of clinical success.
Abstract Lurbinectedin (Zepzelca) is a marine-derived anti-tumor agent currently approved for metastatic small cell lung cancer (SCLC). Lurbinectedin has been previously shown to exert its anti-tumor effect by binding to the minor groove of DNA and inhibition of nucleotide excision repair. In addition, lurbinectedin inhibits transcription by inducing degradation of RNA polymerase II. While these activities hint towards a general mechanism, specific molecular targets for lurbinectedin remain obscure. We demonstrate that in vitro, Lurbinectedin specifically induced downregulation of MCL1 protein, a member of the BCL2 family of pro-survival proteins, in a dose- (0-30 nM) and time-dependent manner (0-24 h) by Western analysis. Expression of other pro-survival proteins BCL2 and BCL2L1 were not affected. The downregulation of MCL1 was consistent in all nine tumor cell lines tested regardless of indication. Increased activity or expression of MCL1 is a known compensatory mechanism to offset loss of BCL2 or BCL2L1. We therefore hypothesized that lurbinectedin induced MCL1 loss, along with inhibition of the pro-survival proteins BCL2 and BCL2L1 would lead to an enhancement in cell killing. Consistent with the dominant pro-survival role of BCL2 in SCLC, the combination of lurbinectedin with a specific BCL2 inhibitor (venetoclax) in vitro induced synergistic cytotoxicity (measured by Bliss Sum analysis) in a panel of small cell lung cancer lines. In solid tumor lines other than SCLC, the combination of lurbinectedin with a specific BCL2L1 inhibitor (A-1331852) was also synergistic. Correspondingly in vivo, enhancement in the efficacy of lurbinectedin was observed in combination with venetoclax in SCLC models, while in solid tumor models other than SCLC the combination with a specific BCL2L1 inhibitor enhanced efficacy. Collectively, these data identify MCL1 as a specific lurbinectedin target and suggest that combinations that target other pro-survival proteins may represent a viable strategy to enhance the anti-tumor activity of lurbinectedin. Citation Format: Kedar S. Vaidya, Aparna Gupta, Robert Hauptschein, Robin C. Humphreys. Lurbinectedin exhibits combinatorial activity with BCL2/BCL2L1 inhibitors in vitro and in vivo by modulation of MCL1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6155.
The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.
