The US Food and Drug Administration (FDA) has cleared two Investigational New Drug (IND) applications from Cambridge, Massachusetts-based biotech Pyxis Oncology, allowing the company to initiate Phase 1 clinical trials.
PYX-201, a novel, non-internalized, antibody-drug conjugate (ADC) drug candidate. The investigational agent is composed of a human IgG1 anti-fibronectin extra-domain B monoclonal antibody conjugated to auristatin utilizing the Flexible Antibody Conjugation Technology (FACT) platform in-licensed from Pfizer, via a cathepsin B-cleavable linker.
PXY-201 will be investigated for the potential treatment of several solid tumors, including breast, head and neck, lung, and thyroid cancer.
The Extra domain B splice variant of fibronectin is an extracellular matrix protein (ECM) deposited by tumor-associated fibroblasts, and is associated with tumor growth, angiogenesis, and invasion. 
Researchers at Pfizer, hypothesized that the Extra domain B splice variant of fibronecti is a safe and abundant target for therapeutic intervention with an antibody–drug conjugate (ADC) and contains a domain that is rarely found in healthy adults and is almost exclusively expressed by newly formed blood vessels in tumors, particularly in solid tumors, different types of lymphoma and some leukemia. Based on the available data, the extra domain B splice of fibronectin has broad therapeutic potential.
PYX-106, an immunotherapy product candidate, will be investigated for the potential treatment of solid tumors, including bladder, cholangio-carcinoma, colorectal, and kidney cancer.
In preclinical studies, the FACT platform technology has demonstrated a superior therapeutic index over currently marketed auristatin based ADCs. FACT site-specific conjugation of vc-0101 to engineered cysteine residues exhibits improved therapeutic Index over ado-trastuzumam emtansine (Kadcyla®; Genentech/Roche) and conjugation technology used in brentuximab vedotin (Adcetris®; Seagen) and enfortumab vedotin (Padcev®; Astellas Pharma/Seagen) Finally, Phase 1 dose-escalation study of a novel anti- HER2 ADC constructed using the FACT platform showed promising efficacy and generally manageable toxicity profile at doses significantly higher than currently approved auristatin ADCs
“We are thrilled to receive two nearly simultaneous IND clearances from the FDA, representing a major moment as we transition to a clinical stage company demonstrating the operational prowess of our team,” said Lara Sullivan, M.D., President and Chief Executive Officer of Pyxis Oncology.
“We are proud of both the substantial clinical IND execution capabilities of our organization and the recent expansion of exclusivity of our ADC technology toolkit with Pfizer, both of which solidify Pyxis Oncology as a leading emerging clinical company. We believe the combination of our veteran leadership team and our cash runway into the first half of 2025 positions us to advance these potentially important therapies for patients who desperately need new options.”
“We are excited to advance multiple programs to the clinic. Both product candidates could potentially be applied to a broad range of tumors and address a significant need in the community,” noted Jay Feingold, M.D., Ph.D., Chief Medical Officer of Pyxis Oncology.
“PYX-201 represents a new potential class of ADCs with a multifaceted mechanism of action which targets a component of the tumor microenvironment that is highly expressed in a variety of solid tumors,” he added.
“In patient-derived xenograft (PDX) model studies of NSCLC and pancreatic cancer, the ADC delivered a highly potent payload that was shown to attack the tumor and associated cells directly in a dose-dependent manner. PYX-106 is a potential immunotherapy that has demonstrated strong activity in preclinical studies and binds to an immune-regulatory receptor, Siglec-15, that has been shown to have an immune suppressive function and shares little overlap with the most prominent IO targets, the PD-1/PDL-1 pathway. The antibody’s strong activity and its target’s unique expression suggest that PYX-106 could be valuable in both mono and combination treatment settings for a broad range of tumors. We look forward to beginning both clinical trials in early 2023,” Feingold said.
PYX-201 is a non-internalizing ADC product candidate that binds to extradomain-B (EDB) fibronectin, an integral component of the extracellular matrix in the tumor that is overexpressed in many malignancies and is minimally expressed in most normal adult tissues. As shown in patient-derived xenograft (PDX) model studies of NSCLC and pancreatic cancer, its highly cell-permeable auristatin payload is enzymatically released after binding, which directly attacks cancer cells and other components that form the supportive tumor infrastructure. Auristatin elicits an antitumor immune response by inducing immunogenic cell death and dendritic cell maturation. While its effects are primarily due to its non-internalizing activity, a fraction of PYX-201 may also be internalized, further enhancing its antitumor activity.
The first-in-human trial of PYX-201 will be a dose escalation trial to determine the recommended phase 2 dose. The study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with solid tumors known to have significant expression of EDB of fibronectin.
PYX-106 is an immunotherapy product candidate in development that blocks the activity of Siglec-15, an emerging immune suppressor expressed across a broad range of tumors. Siglec-15 expression does not overlap with one of the most common targets in immuno-oncology, PD-1, supporting its potential use alone and in combination with current immunotherapies. PYX-106 may benefit patients who do not respond to current standards of care. In preclinical studies, PYX-106 has demonstrated broad immune activation, strong binding affinity, and a 7-day half-life. Cumulatively, these advantages may translate to superior anticancer activity and more flexible dosing regimens.
The first-in-human trial of PYX-106 will be a dose escalation trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with tumors known to have significant infiltration of M2 macrophages and expression of Siglec-15 in order to determine the recommended phase 2 dose.
Paused and closed ADC program
In addition to PYX-201 and PYX-106, Pyxis Oncology was also developing the investigational ADCs, including PYX-202 and PYX-203.
PYX-202 is an ADC, in-licensed from LegoChem Biosciences, targeting DLK1 (delta-like 1 homolog (Drosophila)), a tumor cell surface antigen that is expressed in a range of solid tumors. DLK1 is a one-time transmembrane membrane protein consisting of 383 amino acids in total length, and the protein is 6 EGF-like repeats in the extracellular region and is widely expressed during fetal development. This expression is, however, highly restricted in adults. DLK-1 is an attractive target for ADC development because it is expressed in adults in several tumors, including neuroblastoma, hepatocellular carcinoma (HCC), small cell lung cancer (SCLC), and acute myeloid leukemia (AML).
This investigational agent is designed to reduce toxicity by using a highly stable linker and Monomethyl Auristatin E (MMAE), a well-understood cytotoxic agent. However, following evaluations GLP and non-GLP toxicology studies on PYX-202 to determine the clinical viability of the drug candidate, Pyxis Oncology permanently stoped the development of PYX-202 in August 2022. And while preclinical data suggests DLK1 has the potential to be a novel therapeutic target in the treatment of small-cell lung cancer and soft tissue sarcoma, Pyxis Oncology has agreed to evaluate the potential of other DLK1-ADC candidates in development at LegoChem that feature LegoChem’s proprietary next-generation payloads.
PYX-203 is an ADC designed for the treatment of hematologic cancers and targets and binds to the interleukin-3 receptor, also known as CD123, a rapidly internalizing target that is overexpressed in hematologic cancers by leukemic blasts and stem cells. After internalization, its highly potent cyclopropylpyrroloindoline (CPI) payload is enzymatically released and trafficked to the nucleus, where it crosslinks DNA interstrands. CPI is engineered for enhanced tolerability and may allow PYX-203 to reach a broader patient population. CPI is resistant to drug efflux pumps and could confer superior cancer-killing activity. The antibody is also engineered to have a modified Fc region to mitigate off-tumor toxicity.
And, as reported in August 2022, while the company paused the preclinical development of PYX-203, Pyxis Oncology remains optimistic about the long-term clinical promise of this investigational drug and is considering both strategic collaboration and licensing opportunities and potential future in-house development to maximize value for this program.
Both PYX-201 and PYX-203 are in-licensed from Pfizer.
Study of PYX-201 in Solid Tumors – NCT05720117
Study of PYX-106 in Solid Tumors – NCT05718557
Highlights of prescribing information
Ado-trastuzumam emtansine (Kadcyla®; Genentech/Roche)[Prescribing Information]
Brentuximab vedotin (Adcetris®; Seagen)[Prescribing Information]
Enfortumab vedotin (Padcev®; Astellas Pharma/Seagen)[Prescribing Information]
 Lieverse RIY, Marcus D, van der Wiel AMA, Van Limbergen EJ, Theys J, Yaromina A, Lambin P, Dubois LJ. Human fibronectin extra domain B as a biomarker for targeted therapy in cancer. Mol Oncol. 2020 Jul;14(7):1555-1568. doi: 10.1002/1878-0261.12705. Epub 2020 Jun 15. PMID: 32386436; PMCID: PMC7332215.
 Hooper AT, Marquette K, Chang CB, Golas J, Jain S, Lam MH, Guffroy M, Leal M, Falahatpisheh H, Mathur D, Chen T, Kelleher K, Khandke K, Muszynska E, Loganzo F, Rosfjord E, Lucas J, Kan Z, Subramanyam C, O’Donnell C, Neri D, Gerber HP, May C, Sapra P. Anti-Extra Domain B Splice Variant of Fibronectin Antibody-Drug Conjugate Eliminates Tumors with Enhanced Efficacy When Combined with Checkpoint Blockade. Mol Cancer Ther. 2022 Sep 6;21(9):1462-1472. doi: 10.1158/1535-7163.MCT-22-0099. PMID: 35793468; PMCID: PMC9446899.
Featured image: FDA Sign. Photo courtesy: © 2016 – 2023. Fotolia/Adobe. Used with permission.