Research & Development
Alpine Immune Sciences Advances Oncology Programmes with New ALPN-202 Preclinical Data
13 November 2018 - - US-based immunotherapy company Alpine Immune Sciences, Inc. (NASDAQ: ALPN) has advanced its oncology programme, the company said.

Following promising preclinical data presented TODAY at the Society for Immunotherapy of Cancer 33rd annual meeting in Washington, DC, the company remains on track to initiate human clinical trials of ALPN-202, a PD-L1/CTLA-4 dual antagonist with PD-L1 dependent CD28 costimulation, in the fourth quarter of 2019. Additionally, Alpine has strengthened its Scientific advisory board with the addition of key oncology leaders Rafi Ahmed, Ph.D., James Welsh, M.D., and John Thompson, M.D.

Alpine presented the results of a preclinical study of ALPN-202 in a poster session, strongly supporting the proposed mechanism of action of ALPN-202 via activation of the immune system in a differentiated way from current checkpoint therapies.

ALPN-202 is a novel molecule designed to block the inhibitory immune checkpoints PD-L1 and CTLA-4 while providing PD-L1 dependent T cell activation via the CD28 costimulatory pathway. It has previously been demonstrated to have efficacy in an MC38-based colorectal cancer model, superior to the FDA-approved PD-L1 inhibitor durvalumab.

This poster correlates these findings with superior intratumoral immune cell infiltration and effector gene signatures, as well as favorable changes in T cell receptor profiles, consistent with ALPN-202's proposed multi-modal mechanism of action.

The preclinical study evaluated the anti-tumor responses of ALPN-202 compared with durvalumab in mice implanted with human PD-L1 transduced MC38 tumors.

Results showed ALPN-202 produced dose-dependent anti-tumor responses, including potent single-dose activity, induced a greater tumor inflammation gene signature than durvalumab, induced increased T cell infiltration and T cell-related effector gene signatures compared to durvalumab and promoted both increased T cell receptor clonality and richness, consistent with ALPN-202's multiple mechanisms of action.

NKp30/ICOSL vIgD-Fc program demonstrates tumor-localized costimulation

In a second preclinical study, Alpine used its variant immunoglobin domain platform to engineer novel NKp30/ICOSL vIgD fusion proteins.

The resulting therapeutic is designed to agonize two T cell costimulatory receptors ICOS and CD28 only in the presence of B7-H6, a tumor antigen overexpressed in certain cancer types such as some forms of esophageal, kidney, rectal, and stomach cancers.

Results showed the NKp30-ICOSL vIgD-Fc fusion proteins conferred potent T cell costimulation in vitro, with enhanced T cell proliferation and cytokine production only in response to B7-H6-expressing target cells.

In contrast, ICOSL and NKp30 vIgDs alone in the absence of B7-H6 were not inflammatory.

Demonstrated efficacy in a B7-H6-positive CT26 mouse colon cancer model, especially when administered in combination with a PD-1 inhibitor. The proteins were not effective on a B7-H6-negative parental CT26 tumors, demonstrating target specificity.

Alpine Immune Sciences is focused on leading a new wave of functional immune therapeutics. Alpine is employing directed evolution to create potentially powerful multifunctional immunotherapies to improve patients' lives.

Supported by promising preclinical data, we aim to have two programs in the clinic in 2019. The first, ALPN-101 for autoimmune/inflammatory diseases, is a dual ICOS/CD28 antagonist, engineered to reduce pathogenic immune responses.

The second, ALPN-202 for cancer, is a dual PD-L1/CTLA-4 antagonist and PD-L1-dependent CD28 T cell costimulator intended to combine checkpoint inhibition with a necessary costimulation signal an approach currently absent from approved checkpoint therapies.
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