Strategic target selection for pyrrolobenzodiazepine (PBD)-based antibody drug conjugates (ADCs) and substantial investment in early clinical development have enabled ADC Therapeutics to build a deep clinical and research pipeline of therapies for the treatment of hematologic and solid tumor cancers with significant unmet need.
Loncastuximab tesirine-lpyl is an ADC composed of a humanized monoclonal antibody that binds to human CD19 and is conjugated through a linker to a PBD–dimer toxin. Once bound to a CD19-expressing cell, loncastuximab tesirine-lpyl is internalized into the cell, where enzymes release the PBD-based warhead. The warhead is designed to bind irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication. This ultimately results in cell death.
The LOTIS clinical trial program
Camidanlumab tesirine is in development for classic Hodgkin Lymphoma. It has demonstrated significant clinical activity in heavily pretreated patients with cHL during Phase 2 study.
Camidanlumab tesirine targets CD25
Camidanlumab tesirine is an ADC composed of a monoclonal antibody that binds to CD25 (HuMax®-TAC, licensed from Genmab A/S), conjugated to a PBD–dimer toxin. Once bound to a CD25-expressing cell, Camidanlumab tesirine is internalized into the cell where enzymes release the PBD-based warhead. In addition to CD25-expressing tumor cells, Camidanlumab tesirine depletes CD25-positive Tregs in the local tumor environment, which enhances immune-mediated anti-tumor activity.
ADCT-602 targeting CD22
ADCT-602 is an ADC composed of a monoclonal antibody that binds to CD22 conjugated to a PBD–dimer toxin. Once bound to a CD22-expressing cell, ADCT-602 is internalized into the cell where enzymes release the PBD-based warhead. CD22 is an attractive and clinically validated ADC target. CD22 is highly expressed on most malignant B-cells, including expression in more than 90% of patients with B-cell acute lymphoblastic leukemia (ALL).
ADCT-602 is being evaluated in a phase I/II clinical trial in patients with relapsed or refractory B-cell ALL (NCT03698552). The trial is being led by The University of Texas MD Anderson Cancer Center.
Mipasetamab uzoptirine (ADCT-601)
Mipasetamab uzoptirine (ADCT-601) is an ADC composed of a humanized monoclonal antibody that binds to human AXL (licensed from BerGenBio), conjugated using GlycoConnect™ technology (licensed from Synaffix BV) to a linker with the PBD–dimer toxin SG3199. Once bound to a cell that expresses the AXL protein, Mipasetamab uzoptirine (ADCT-601) is internalized, the PBD is released and diffuses into the nucleus where it binds the DNA. AXL is a promising target for an ADC approach, as it is overexpressed in many solid tumors (e.g., sarcoma, lung, breast, prostate, pancreas, glioma, and esophageal) and hematological malignancies (e.g., acute and chronic myeloid leukemia).
ADCT-901 targeting KAAG1
ADCT-901 is an ADC composed of a humanized monoclonal antibody (3A4) directed against human KAAG1 and conjugated through a cathepsin-cleavable linker to SG3199, a PBD–dimer cytotoxin. KAAG1 is an attractive novel tumor target for ADC development because it has high expression in tumor cell lines, including ovarian cancer and triple negative breast cancer, and low expression on non-cancerous cells from the same tissue. The ADC is internalized and has been shown to be an effective cytotoxin in various preclinical models.
ADCT-901 is being developed for the treatment of advanced solid tumors with high unmet medical needs, including platinum resistant ovarian cancer and triple negative breast cancer.
ADCT-701 targeting DLK-1
We are collaborating on the development of ADCT-701 with the National Cancer Institute (NCI), which is part of the National Institutes of Health (NIH) in the United States. ADCT-701 is an ADC composed of a humanized monoclonal antibody (HuBa-1-3D) directed against human DLK-1 and conjugated through a cathepsin-cleavable linker to SG3199, a PBD–dimer cytotoxin. DLK-1 is widely expressed during fetal development, and it is an attractive target for ADC development because in adults it is expressed in neuroendocrine and other tumors, such as neuroblastoma, hepatocellular carcinoma (HCC), small cell lung cancer (SCLC), and acute myeloid leukemia (AML).
ADCT-701 is being developed for the treatment of advanced solid tumors of neuroendocrine origin. This project is in the pre (investigational new drug) IND stage.
ADCT-212 is a second-generation PBD-based ADC targeting prostate-specific membrane antigen (PSMA). PSMA is a well-validated target for prostate cancer and utilizes a PBD known as SG2000. ADCT-212 shows strong activity in in vivo models, with good tolerability and exposure. ADCT-212 also incorporates technology from GlycoConnect™ and Hydraspace™ (licensed from Synaffix BV). This technology is also used in ADCT-601 and ADCT-701. We are currently conducting preclinical studies to support an Investigational New Drug (IND) filing for ADCT-212.