NextCure and LCB Present Preclinical Data on B7-H4 Antibody Drug Conjugate at AACR 2024
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Insights
The development of LNCB74 represents a significant step in the field of targeted cancer therapy. The emphasis on a B7-H4 targeting antibody drug conjugate (ADC) is noteworthy, as B7-H4 is known to be overexpressed in various solid tumors. The ability of LNCB74 to specifically target and bind to tumor cells expressing B7-H4 and its internalization in a target-dependent manner, is an innovative approach that could offer a more focused treatment, potentially reducing the side effects associated with broader-acting chemotherapeutics.
Furthermore, the use of LigaChem Biosciences' proprietary site-specific conjugation and plasma-stable linker technology is a sophisticated technique that may improve the delivery of the cytotoxic agent, monomethyl auristatin E (MMAE), to the cancer cells while minimizing systemic toxicity. The reported preclinical safety and pharmacokinetic profiles are promising, indicating that the ADC has a favorable therapeutic index. The reported EC50 values, which measure the concentration of the drug needed to kill half the cancer cells in vitro, suggest that LNCB74 is highly potent against B7-H4-positive cancer cell lines.
From a pharmacokinetic perspective, the favorable profile of LNCB74 in rodents is an encouraging indicator of its potential in humans. The stability of the ADC in serum and its pharmacokinetic activity are critical for ensuring that the drug remains effective throughout the body until it reaches the tumor site. The drug-to-antibody ratio (DAR) of 4 suggests a substantial payload per antibody, which could enhance the drug's efficacy while still maintaining a manageable safety profile.
The tolerability observed in cynomolgus monkeys, which are often used as a model for predicting human responses, suggests that the ADC may have a lower risk of adverse effects in humans. This aspect is particularly important as it may allow for higher dosing or more prolonged treatment regimens, potentially leading to better clinical outcomes. The pharmacokinetics of LNCB74 will be a key factor in its clinical development, as it will influence dosing schedules and the design of clinical trials.
The translation of preclinical findings to clinical efficacy is not always straightforward, but the promising data presented for LNCB74 sets the stage for its clinical development. The reported durable tumor regression in CDX and PDX tumor models after a single 3 mg/kg dose is particularly impressive and suggests that LNCB74 could have a strong impact on tumor control. If these results can be replicated in humans, LNCB74 could potentially outperform existing B7-H4 targeting ADCs, which would be a significant achievement in oncology.
As the drug advances to clinical trials, the design of these studies will need to carefully consider the preclinical data to optimize the chances of success. The selection of endpoints, dosing strategies and patient populations will be crucial. For instance, the inclusion of biomarker analysis to confirm B7-H4 expression in tumors could be essential for patient stratification. The preclinical safety and efficacy data provide a solid foundation for the clinical trial protocol and will be instrumental in discussions with regulatory agencies.
Poster presentation highlights strong safety and pharmacokinetic profiles for LNCB74
BELTSVILLE, Md., April 08, 2024 (GLOBE NEWSWIRE) -- NextCure, Inc. (Nasdaq: NXTC), a clinical-stage biopharmaceutical company committed to discovering and developing novel, first-in-class and best-in-class therapies to treat cancer, today announced the presentation of new preclinical data on LNCB74, a B7-H4-targeting antibody drug conjugate (ADC) developed in partnership with LigaChem Biosciences (LCB), formerly LegoChem Biosciences, (KOSDAQ: 141080), at the 2024 American Association for Cancer Research (AACR) Annual Meeting in San Diego, CA. The poster presentation highlights LNBC74’s promising preclinical safety and anti-tumor activity.
LNCB74 is an ADC utilizing LigaChem Biosciences’ proprietary site-specific conjugation and plasma-stable, cancer selectively activating linker technology to link monomethyl auristatin E (MMAE) to a B7-H4 targeting antibody in a drug-to-antibody ratio of 4 (DAR4). The presentation includes data demonstrating LNCB74’s high affinity and specificity for human B7-H4, a protein highly expressed on a range of solid tumors including breast, ovarian and endometrial cancers. LNCB74 was shown to specifically bind to B7-H4 expressing tumor cells and was rapidly internalized in a target-dependent manner. In addition, data showed that LNCB74 mediated potent cytotoxicity in B7-H4-positive cancer cells in vitro and demonstrated serum stability with a favorable pharmacokinetic (PK) activity in rodents. LNCB74 demonstrated significant tolerability in cynomolgus monkeys and showed strong anti-tumor activity in multiple cell-line derived (CDX) and patient-derived xenograft (PDX) tumor models in vivo. The increase in tolerability and strong efficacy is expected to translate into clinical activity of LNCB74.
“LNCB74 was developed through NextCure’s expertise in B7-H4 tumor biology and LCB’s ConjuAllTM technology, resulting in a potent ADC with initial data demonstrating excellent tolerability and pharmacokinetics,” said Solomon Langermann, Ph.D., NextCure’s chief scientific officer. “These data underscore that LNCB74 is a promising candidate for the treatment of a variety of solid tumor indications. We look forward to continuing our work building a robust preclinical dataset to further support advancing this ADC to the clinic.”
Key Findings:
- LNCB74 was engineered for an improved safety profile and therapeutic index with increased stability in circulation, tumor selective payload release, and a reduction in off-target release of active payload, mitigating toxicity compared to traditional vedotin ADCs.
- A single 3 mg/kg dose of LNCB74 resulted in durable tumor regression in multiple CDX and PDX tumor models, suggesting activity comparable or superior to competitor B7-H4 targeting ADCs.
- LNCB74 was well tolerated in cynomolgus monkeys following 2 doses of up to 10 mg/kg, showing a superior safety profile compared to traditional MMAE bearing ADCs.
- LNCB74 demonstrates favorable pharmacokinetics and stability in rodents, consistent with the molecule’s preclinical safety profile.
- LNCB74 mediates potent cytotoxicity, with sub-nanomolar to low nanomolar EC50 values on multiple B7-H4-positive cancer cell lines.
Details of the presentation are as follows:
Title: LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers
Date and Time: April 8, 2024, 9:00am-12:30pm PT
Session: Antibody-Drug Conjugates and Bispecific Antibodies
Abstract Number: 1898
About NextCure, Inc.
NextCure is a clinical-stage biopharmaceutical company that is focused on advancing innovative medicines that treat cancer patients that do not respond to, or have disease progression on, current therapies, through the use of differentiated mechanisms of actions including antibody-drug conjugates, antibodies and proteins. We focus on advancing therapies that leverage our core strengths in understanding biological pathways and biomarkers, the interactions of cells, including in the tumor microenvironment, and the role each interaction plays in a biologic response. www.nextcure.com
About LigaChem Biosciences, Inc.
LigaChem Biosciences (formerly LegoChem Biosciences, Inc.) is a clinical stage biopharmaceutical company dedicated to the discovery and development of innovative medicines by leveraging our medicinal chemistry expertise to make conventional biologics more targeted and potent for the benefit of patients with diseases of highly unmet medical needs. We are advancing sustainable pipelines in therapeutic areas within antibiotics, anti-fibrotics, oncology, and antibody-drug conjugate platform technology. www.legochembio.com
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Investor Inquiries
Timothy Mayer, Ph.D.
NextCure, Inc.
Chief Operating Officer
(240) 762-6486
IR@nextcure.com
FAQ
What is the name of the B7-H4-targeting antibody drug conjugate presented by NextCure, Inc.?
What technology was utilized to link monomethyl auristatin E to the B7-H4 targeting antibody in LNCB74?
Which protein is highly expressed on a range of solid tumors and targeted by LNCB74?
What type of activity did LNCB74 demonstrate in B7-H4-positive cancer cells in vitro?
What key findings were highlighted in the poster presentation regarding LNCB74?
