drozitumab (RG7425) / Roche - LARVOL DELTA

Combination of multivalent DR5 receptor clustering agonists and histone deacetylase inhibitors for treatment of colon cancer. (PubMed, J Control Release) - "In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering...Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy."

Epigenetic controller • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • TNFA • TNFRSF10B

Arguments for the involvement and importance of cells of the tumor microenvironment as additional drivers of tumor growth (DGHO 2024) - "ADC relevant drugs have been approved such as e.g. Trastuzumab deruxtecan for HER+ and low Her2+ breast cancer, for Her2 mutant NSCLC, for Her2+ gastric cancer, the anti-Trop-2 antibody sacituzumab coupled to govitecan (SG) for triple- and HR+, Her2- breast cancer (3), or the anti-nectin 4 antibody, coupled to monomethyl auristatin E (MMAE) for urothelial carcinona (4)...With regard to tumor associated macrophages it was shown that the dead tumor cell-targeting APOMAB antibody conjugated to tesirine (SG3249) was effective in lung cancer models when given after chemotherapy (8)... Tumor growth can be modulated through impairment of several TME cells. This effect can be aggravated by releasing a cytotoxic payload to cells in the TME. A better definition of the functional state of those apparently non malignant, however tumor growth supporting cells in the TME demands further investigations."

Biomarker • Tumor microenvironment • Breast Cancer • Colon Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

A Study of PRO95780 in Patients With Advanced Chondrosarcoma (APM4171g) (clinicaltrials.gov) - P2 | N=15 | Terminated | Sponsor: Genentech, Inc. | N=90 ➔ 15

Enrollment change • Oncology • Sarcoma • Solid Tumor

Fc gamma receptor is not required for in vivo processing of radio- and drug-conjugates of the dead tumor cell-targeting monoclonal antibody, APOMAB®. (PubMed, Biomed Pharmacother) - "Also, the post-chemotherapy activity of a chDAB4-antibody drug conjugate (ADC) directed against LL2 tumors did not differ among tumor-bearing wild-type, Fcγ KO and NOTAM mice, nor did the proportions and characteristics of the LL2 tumor immune cell infiltrates differ significantly among these mice. In conclusion, Fc-FcγR interactions are not essential for the diagnostic or therapeutic applications of chDAB4 conjugates because the tumor-associated macrophages, which engulf the chDAB4-labelled dead cells, respond to endogenous 'eat me' signals rather than depend on functional FcγR expression for phagocytosis."

Journal • Preclinical • Hematological Malignancies • Lung Cancer • Lymphoma • Oncology

The RNA-binding protein La/SSB associates with radiation-induced DNA double-strand breaks in lung cancer cell lines. (PubMed, Cancer Rep (Hoboken)) - "The co-localisation of La/SSB with radiation-induced DNA breaks suggests a role of La/SSB in DNA repair, however further experimentation is required to validate this."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RAD51

Positron Emission Tomographic Imaging of Tumor Cell Death Using Zirconium-89-Labeled APOMAB® Following Cisplatin Chemotherapy in Lung and Ovarian Cancer Xenograft Models. (PubMed, Mol Imaging Biol) - "Given that tumors, rather than normal tissues, were targeted after chemotherapy, these results support the clinical development of chDAB4 as a radiodiagnostic imaging agent and as a potential predictive marker of treatment response."

Journal • Preclinical • Immunology • Inflammatory Arthritis • Lung Cancer • Lupus • Oncology • Ovarian Cancer • Solid Tumor

Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®. (PubMed, EJNMMI Radiopharm Chem) - "ImmunoPET using chDAB4 radiolabeled with residualizing [Zr] Zr rather than [I] I optimized post-chemotherapy tumor uptake. Further, PET imaging characteristics were improved by DFOSq rather than DFO-NCS. Therefore, the radionuclide/chelator combination of [Zr] Zr and DFOSq is preferred for the imminent clinical evaluation of chDAB4 as a selective tumor cell death radioligand."

Journal • Hematological Malignancies • Hepatology • Immunology • Inflammatory Arthritis • Lupus • Lymphoma • Oncology • Sjogren's Syndrome

Tumour-associated macrophages process drug and radio-conjugates of the dead tumour cell-targeting APOMAB® antibody. (PubMed, J Control Release) - "The tumour uptake of Zr-chDAB4 was reduced after macrophage depletion, which also reduced the efficacy of the chDAB4 ADC in vivo. This study shows that macrophages can process chDAB4 and chDAB4 ADC in vitro and shows the importance of tumour-associated macrophages in the tumour retention of chDAB4 and the efficacy of chDAB4 ADC in vivo."

Journal • Lung Cancer • Oncology

Pancreatic cancer stem cells in patient pancreatic xenografts are sensitive to drozitumab, an agonistic antibody against DR5. (PubMed) - J Immunother Cancer - "Overall, our work reveals that treatment of pancreatic tumors with the drozitumab can lead to long-term tumor control by targeting both bulk cells and CSCs."

Journal • Biosimilar • Gastrointestinal Cancer • Gene Therapies • Graft versus Host Disease • Oncology • Pancreatic Cancer

Targeting Mind Bomb-2 and MIP, new Regulators of Tumour cell Survival in TRAIL Signaling (LCC 2020) - "Activating the “extrinsic” apoptotic pathway, selectively in cancer cells, both with the recombinant human ligand (rhTRAIL) or agonistic antibodies (Mapatumumab, Apomab) has therefore been a goal of cancer researchers and pharmaceutical companies for many years. Furthermore, we assess the therapeutic potential of targeting these molecules for cancer treatment in combination with TRAIL and provide proof of principle evidence that targeting these molecules can have clinical utility. Using Proteolysis targeting chimera (PROTAC) approach we show that MIP and MIB2 can be degraded using available PROTAC drugs."

Implementing Patient-Derived Xenografts to Assess the Effectiveness of Cyclin-Dependent Kinase Inhibitors in Glioblastoma. (PubMed, Cancers (Basel)) - "Here, we have assessed the efficacy of seliciclib when delivered in combination with the antibody against human death receptor 5, drozitumab, in clinically relevant patient-derived xenograft (PDX) models of GBM. Additional studies showed that the second-generation CDK inhibitor, CYC065, with improved potency in comparison to seliciclib, induced a significant decrease in the size of human GBM neurospheres in vitro and was well tolerated in vivo, upon administration at clinically relevant doses. This study highlights the continued need for robust pre-clinical assessment of promising treatment approaches using clinically relevant models."

Clinical • Journal

APOMAB® antibody drug conjugates targeting dead tumor cells are effective in vivo. (PubMed, Mol Cancer Ther) - "Rather than targeting a tumor cell type-specific antigen, DAB4-ADCs have the advantage of targeting a common trait in most solid tumors: an excess of post-apoptotic, necrotic cells either adjacent to hypoxic tumor regions or distributed more generally after cytotoxic therapy. Consequently, any antitumor effects are solely the result of bystander killing, either through internalization of the dead, ADC-bound tumor cells by macrophages or extracellular cleavage of the ADC in the tumor microenvironment."

Journal • Preclinical