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. CD19 is a clinically validated target for the treatment of B-cell malignancies.
The LOTIS clinical trial program
Camidanlumab tesirine is ADCT’s second lead candidate. It has demonstrated significant clinical activity in heavily pretreated patients with Hodgkin lymphoma. Based on its mechanism targeting CD25/regulatory T cells, camidanlumab tesirine is also demonstrating potential in the treatment of solid tumors.
Camidanlumab tesirine targets CD25/regulatory T cells
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.
Camidanlumab tesirine is being evaluated in several clinical trials
Studies include a pivotal phase 2 clinical trial in patients with relapsed or refractory (R/R) Hodgkin lymphoma (NCT04052997); a phase 1a/1b clinical trial in patients with R/R Hodgkin lymphoma and Non-Hodgkin lymphoma (NCT02432235); and a phase 1b clinical trial in solid tumors (NCT03621982).
The clinical development of this product is ongoing. Camidanlumab tesirine (ADCT-301) is an investigational agent. The safety and efficacy have not yet been established.
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 a PBD–dimer toxin. Once bound to an AXL-expressing cell, Mipasetamab uzoptirine (ADCT-601) is internalized into the cell, where enzymes release the PBD-based warhead. AXL is an ideal target for an ADC approach, as it is highly overexpressed in many solid tumors (eg, lung, breast, prostate, pancreas, glioma, and esophageal) and hematological malignancies (eg, 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 as (i) it is an intracellular target by definition, but becomes exposed on the membrane of tumor cells, (ii) it has high expression in tumors with high unmet medical need, including ovarian cancer and triple negative breast cancer, while its expression on healthy tissue is very restricted, and (iii) it internalizes and co-localizes with lysosomal-associated membrane protein 1, a lysosomal marker, which shows that the target is efficiently transported to the cellular compartment where efficient release of the cytotoxin is expected.
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; however, its expression is highly restricted in adults. DLK-1 is an attractive novel tumor target for ADC development as it is expressed in adults in several 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 with high unmet medical needs, neuroblastoma, HCC, and SCLC. We are currently preparing for an Investigational New Drug (IND) submission.
ADCT-212 targeting PSMA
ADCT-212 is an optimized, second-generation PBD-based ADC targeting prostate-specific membrane antigen (PSMA). PSMA is a well-validated target for prostate cancer. Since PSMA is known to be expressed in the neovasculature of numerous solid tumors, there may be other applications of this ADC. ADCT-212 has a much better profile than the first-generation PBD-based ADC (known as MEDI3726) as optimizations in the antibody and the PBD dimer toxin have resulted in strong activity in in vivo models, with increased 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.