NextCure reports data from LNCB74, NC410 studies

NextCure (NXTC) reported pre-clinical data from LNCB74, a B7-H4-targeting antibody-drug conjugate, or ADC, being developed in partnership with LigaChem Biosciences, and biomarker data from the NC410 combination study with pembrolizumab in patients with immune checkpoint inhibitor naive and refractory microsatellite stable/microsatellite instability-low colorectal cancer. The data will be presented during poster sessions at the Society for Immunotherapy of Cancer annual meeting. LNCB74 is a B7-H4 antibody conjugated to the microtubule disrupting payload monomethyl auristatin E with a drug-to-antibody ratio of 4. The ADC employs a glucuronidase-cleavable, site-specific linkage conjugated to an engineered cysteine in the antibody light chain via LigaChem Biosciences’ ConjuAll technology to increase stability in circulation, improve selective release of payload in tumor cells, and reduce payload release in non-tumor cells. LNCB74 incorporates an Fc mitigating mutation to minimize binding and uptake of LNCB74 by Fc receptor expressing immune cells. The ConjuAll technology, with its selective cleavage and release within tumor cells, combined with mitigation of off-target uptake via disabled Fc interactions, is engineered to improve the safety profile and therapeutic index of LNCB74 compared to other B7-H4 targeted ADCs. B7-H4 protein is highly expressed in multiple tumor indications. B7-H4 expression limited in normal healthy human tissues, providing a potential broad therapeutic index for a B7-H4 targeting ADC. LNCB74 shows specific binding to B7-H4 expressing tumor cells and is rapidly internalized in a target-dependent manner by cancer cells. LNCB74 mediates potent cytotoxicity, with sub-nanomolar to low nanomolar EC50 values on multiple B7-H4-positive cancer cell lines. LNCB74 demonstrates strong anti-tumor activity in multiple CDX and PDX tumor models. A single dose of 3 mg/kg resulted in durable tumor regression in multiple tumor models, suggesting activity comparable or superior to published B7-H4 targeting ADCs. LNCB74 demonstrates favorable PK and stability in rodents. LNCB74 was well tolerated in cynomolgus monkeys up to 10 mg/kg. The presentation includes additional clinical data for CRC patients from the Phase 1b portion of a Phase 1b/2 study evaluating NC410, a LAIR-2 fusion protein, in combination with pembrolizumab. The trial is evaluating the combination in ovarian cancer and ICI-naive MSS/MSI-L CRC. Overall, the combination of NC410 and pembrolizumab continues to demonstrate clinical activity against MSS/MSI-L CRC, which is generally unresponsive to immunotherapy. Subjects who achieved clinical benefit of partial response or stable disease demonstrated durability of their responses that was clinically meaningful in this patient population. Of the 43 evaluable ICI-naive MSS/MSI-L CRC patients without liver metastasis, there were 3 PRs as of the data cut-off of October 14, 2024. Disease control rates were 86% and 47% for the 200 mg and 100 mg NC410 doses, respectively. Biomarker data support proposed mechanism of action of NC410, showing remodeling of the tumor microenvironment, promotion of immune infiltration and anti-tumor activity. Treatment was well tolerated.