Reference Detail

Ref Type

Journal Article

PMID

(38379869)

Authors

Albu DI, Wolf BJ, Qin Y, Wang X, Daniel Ulumben A, Su M, Li V, Ding E, Angel Gonzalo J, Kong J, Jadhav R, Kuklin N, Visintin A, Gong B, Schuetz TJ

Title

A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncoimmunology	13	1	2024	2316945	Oncoimmunology

URL

Abstract Text

Combinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several in vitro T cell activation assays and outperformed clinically approved benchmarks in the subcutaneous MC38 colon and the B16F10 lung metastasis mouse tumor models. Investigation into the mechanism of action revealed that CTX-8371 co-engagement of PD-1 and PD-L1 induced the proteolytic cleavage and loss of cell surface PD-1, which is a novel and non-redundant mechanism that adds to the PD-1/PD-L1 signaling axis blockade. The combination of CTX-8371 and an agonistic anti-CD137 antibody further increased the anti-tumor efficacy with long-lasting curative therapeutic effect. In summary, CTX-8371 is a novel checkpoint inhibitor that might provide greater clinical benefit compared to current anti-PD-1 and PD-L1 antibodies, especially when combined with agents with orthogonal mechanisms of action, such as agonistic anti-CD137 antibodies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CTX-8371	CTX-8371	2	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CTX-8371		CTX 8371\|CTX8371	Immune Checkpoint Inhibitor 149 PD-L1/PD-1 antibody 122	CTX-8371 is a tetravalent bispecific antibody that targets CD274 (PD-L1) and PDCD1 (PD-1), potentially resulting in enhanced antitumor immune response and inhibition of tumor growth (PMID: 38379869).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CD274 positive	melanoma	sensitive	CTX-8371	Preclinical	Actionable	In a preclinical study, CTX-8371 treatment resulted in fewer lung metastases than either Keytruda (pembrolizumab) or Tecentriq (atezolizumab) monotherapy in a syngeneic mouse model of melanoma expressing CD274 (PD-L1) (PMID: 38379869).	38379869
CD274 positive	colon cancer	sensitive	CTX-8371	Preclinical	Actionable	In a preclinical study, CTX-8371 treatment resulted in greater tumor growth inhibition than either Keytruda (pembrolizumab) or Tecentriq (atezolizumab) in a syngeneic mouse model of colon cancer expressing CD274 (PD-L1), with tumor regression in 62.5% (5/8) of the treated mouse models (PMID: 38379869).	38379869