Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

Background: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902).

Methods: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines.

Tackling the tumor microenvironment - how can complex tumor models aid oncology drug development?

Introduction: Identifying effective cancer drugs remains an inefficient process. Drug efficacy in traditional preclinical cancer models translates poorly into therapy in the clinic. Implementation of preclinical models that incorporate the tumor microenvironment (TME) is needed to improve selection of active drugs prior to clinical trials.

Exploring Metabolic Signatures of Ex Vivo Tumor Tissue Cultures for Prediction of Chemosensitivity in Ovarian Cancer.

Predicting patient response to treatment and the onset of chemoresistance are still major challenges in oncology. Chemoresistance is deeply influenced by the complex cellular interactions occurring within the tumor microenvironment (TME), including metabolic crosstalk. We have previously shown that ex vivo tumor tissue cultures derived from ovarian carcinoma (OvC) resections retain the TME components for at least four weeks of culture and implemented assays for assessment of drug response.

Pathophysiologic and Pharmacologic Considerations to Improve the Design and Application of Antibody-Drug Conjugates.

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.

Application of LDH assay for therapeutic efficacy evaluation of ex vivo tumor models.

The current standard preclinical oncology models are not able to fully recapitulate therapeutic targets and clinically relevant disease biology, evidenced by the 90% attrition rate of new therapies in clinical trials. Three-dimensional (3D) culture systems have the potential to enhance the relevance of preclinical models. However, the limitations of currently available cellular assays to accurately evaluate therapeutic efficacy in these models are hindering their widespread adoption.

Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia.

Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML.

Synergistic therapeutic benefit by combining the antibody drug conjugate, depatux-m with temozolomide in pre-clinical models of glioblastoma with overexpression of EGFR.

Purpose: Depatux-m is an antibody drug conjugate (ADC) that targets and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor (EGFR) or the 2-7 deletion mutant (EGFRvIII) in tumor models in vitro and in vivo. Treatment of patients suffering from relapsed/refractory glioblastoma (GBM) with a combination of depatux-m and temozolomide (TMZ) tended to increase overall survival. As a first step to understand the nature of the interaction between the two drugs, we investigated whether the interaction was synergistic, additive or antagonistic.

Patient-derived ovarian cancer explants: preserved viability and histopathological features in long-term agitation-based cultures.

Ovarian carcinoma (OvC) remains a major therapeutic challenge due to its propensity to develop resistance after an initial response to chemotherapy. Interactions of tumour cells with the surrounding microenvironment play a role in tumour survival, invasion capacity and drug resistance. Cancer models that retain tissue architecture and tumour microenvironment components are therefore essential to understand drug response and resistance mechanisms.

Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X Inhibitor.

Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X inhibitor that selectively and potently induces apoptosis in BCL-X-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-X.

Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate.

ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window.

5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis.

Purpose: Patients with acute myeloid leukemia (AML) frequently do not respond to conventional therapies. Leukemic cell survival and treatment resistance have been attributed to the overexpression of B-cell lymphoma 2 (BCL-2) and aberrant DNA hypermethylation. In a phase Ib study in elderly patients with AML, combining the BCL-2 selective inhibitor venetoclax with hypomethylating agents 5-azacitidine (5-Aza) or decitabine resulted in 67% overall response rate; however, the underlying mechanism for this activity is unknown.

Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate.

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression.

Protocols and characterization data for 2D, 3D, and slice-based tumor models from the PREDECT project.

Two-dimensional (2D) culture of cancer cells in vitro does not recapitulate the three-dimensional (3D) architecture, heterogeneity and complexity of human tumors. More representative models are required that better reflect key aspects of tumor biology. These are essential studies of cancer biology and immunology as well as for target validation and drug discovery.

The Volume of Three-Dimensional Cultures of Cancer Cells InVitro Influences Transcriptional Profile Differences and Similarities with Monolayer Cultures and Xenografted Tumors.

Improving the congruity of preclinical models with cancer as it is manifested in humans is a potential way to mitigate the high attrition rate of new cancer therapies in the clinic. In this regard, three-dimensional (3D) tumor cultures in vitro have recently regained interest as they have been acclaimed to have higher similarity to tumors in vivo than to cells grown in monolayers (2D). To identify cancer functions that are active in 3D rather than in 2D cultures, we compared the transcriptional profiles (TPs) of two non-small cell lung carcinoma cell lines, NCI-H1650 and EBC-1 grown in both conditions to the TP of xenografted tumors.

A "Prozone-Like" Effect Influences the Efficacy of the Monoclonal Antibody ABT-700 against the Hepatocyte Growth Factor Receptor.

ABT-700 is a therapeutic antibody against the hepatocyte growth factor receptor (MET). At doses or regimens that lead to exposures exceeding optimum in vivo, the efficacy of ABT-700 is unexpectedly reduced. We hypothesized that this reduction in efficacy was due to a "prozone-like" effect in vivo.

Drug screening in 3D in vitro tumor models: overcoming current pitfalls of efficacy read-outs.

There is cumulating evidence that in vitro 3D tumor models with increased physiological relevance can improve the predictive value of pre-clinical research and ultimately contribute to achieve decisions earlier during the development of cancer-targeted therapies. Due to the role of tumor microenvironment in the response of tumor cells to therapeutics, the incorporation of different elements of the tumor niche on cell model design is expected to contribute to the establishment of more predictive in vitro tumor models. This review is focused on the several challenges and adjustments that the field of oncology research is facing to translate these advanced tumor cells models to drug discovery, taking advantage of the progress on culture technologies, imaging platforms, high throughput and automated systems.

ABBV-399, a c-Met Antibody-Drug Conjugate that Targets Both -Amplified and c-Met-Overexpressing Tumors, Irrespective of Pathway Dependence.

Despite the importance of the oncogene in many malignancies, clinical strategies targeting c-Met have benefitted only small subsets of patients with tumors driven by signaling through the c-Met pathway, thereby necessitating selection of patients with amplification and/or c-Met activation most likely to respond. An ADC targeting c-Met could overcome these limitations with potential as a broad-acting therapeutic. ADC ABBV-399 was generated with the c-Met-targeting antibody, ABT-700.

Capturing tumor complexity in vitro: Comparative analysis of 2D and 3D tumor models for drug discovery.

Two-dimensional (2D) cell cultures growing on plastic do not recapitulate the three dimensional (3D) architecture and complexity of human tumors. More representative models are required for drug discovery and validation. Here, 2D culture and 3D mono- and stromal co-culture models of increasing complexity have been established and cross-comparisons made using three standard cell carcinoma lines: MCF7, LNCaP, NCI-H1437.

Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models.

BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1.

Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification.

Background: c-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene. Aberrant activation of c-Met resulting from MET amplification and c-Met overexpression is associated with poor clinical outcome in multiple malignancies underscoring the importance of c-Met signaling in cancer progression. Several c-Met inhibitors have advanced to the clinic; however, the development of inhibitory c-Met-directed therapeutic antibodies has been hampered by inherent agonistic activity.

ABT-414, an Antibody-Drug Conjugate Targeting a Tumor-Selective EGFR Epitope.

Targeting tumor-overexpressed EGFR with an antibody-drug conjugate (ADC) is an attractive therapeutic strategy; however, normal tissue expression represents a significant toxicity risk. The anti-EGFR antibody ABT-806 targets a unique tumor-specific epitope and exhibits minimal reactivity to EGFR in normal tissue, suggesting its suitability for the development of an ADC. We describe the binding properties and preclinical activity of ABT-414, an ABT-806 monomethyl auristatin F conjugate.

Adaptable stirred-tank culture strategies for large scale production of multicellular spheroid-based tumor cell models.

Currently there is an effort toward the development of in vitro cancer models more predictive of clinical efficacy. The onset of advanced analytical tools and imaging technologies has increased the utilization of spheroids in the implementation of high throughput approaches in drug discovery. Agitation-based culture systems are commonly proposed as an alternative method for the production of tumor spheroids, despite the scarce experimental evidence found in the literature.