Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity

Kotanides, Helen; Li, Yiwen; Malabunga, Maria; Carpenito, Carmine; Eastman, Scott W.; Shen, Yang; Wang, George; Inigo, Ivan; Surguladze, David; Pennello, Anthony L.; Persaud, Krishnadatt; Hindi, Sagit; Topper, Michael; Chen, Xinlei; Zhang, Yiwei; Bulaon, Danielle Kathryn; Bailey, Tim; Lao, Yanbin; Han, Bing; Torgerson, Stacy; Chin, Darin; Sonyi, Andreas; Haidar, Jaafar N.; Novosiadly, Ruslan D.; Moxham, Christopher M.; Plowman, Gregory D.; Ludwig, Dale L.; Kalos, Michael

doi:10.1158/2326-6066.cir-20-0304

Cited by 43 publications

(34 citation statements)

References 42 publications

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“…These tumor-associated antigen×PD-1/PD-L1 bispecific antibodies might have a great advantage in efficacy and safety. Besides, PD-1 × PD-L1 (LY3434172) and CD47 × PD-L1 (IBI322) bispecific antibodies had enhanced immunomodulatory properties and improved antitumor activity, relative to monospecific PD-1 and PD-L1 antibodies [297,298].…”

Section: Other Bispecific Antibodies Targeting Pd-1/pd-l1mentioning

confidence: 99%

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

et al. 2022

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Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.

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Section: Other Bispecific Antibodies Targeting Pd-1/pd-l1mentioning

confidence: 99%

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

et al. 2022

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“…Immune checkpoints have immunosuppressive regulatory effects, including programmed cell death protein 1 (PD-1) and its ligand programmed cell death protein ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). When immune checkpoints are overexpressed, the immune homeostasis is disrupted and T-cell immune responses were suppressed, leading to immune evasion of tumor cells [ 110 ]. When compared to PD-1 and/or PD-L1 monotherapy, previous preclinical studies have described that BsAbs simultaneously targeting PD-1 and PD-L1 had significant activation of T cells, thus supporting the evaluation of BsAbs targeting immune checkpoints.…”

Section: Targeting Antigensmentioning

confidence: 99%

“…One arm of LY3434172 blocks the binding of PD-1 to PD-L1 and PD-L2, while the other arm blocks the binding of PD-L1 to PD-1 and the agonist receptor, CD80. It has been demonstrated that LY3434172 resulted in robust antitumor activity at doses substantially lower than either parent antibody or their combination in established human xenograft models [ 110 ]. A phase 1 study (NCT03936959) of LY3434172 monotherapy in metastatic solid cancers was completed.…”

Section: Targeting Antigensmentioning

confidence: 99%

Recent advances and challenges of bispecific antibodies in solid tumors

Zhu

et al. 2021

Exp Hematol Oncol

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Cancer immunotherapy has made remarkable progress in the past decade. Bispecific antibodies (BsAbs) have acquired much attention as the next generation strategy of antibody-target cancer immunotherapy, which overwhelmingly focus on T cell recruitment and dual receptors blockade. So far, BsAb drugs have been proved clinically effective and approved for the treatment of hematologic malignancies, but no BsAb have been approved in solid tumors. Numerous designed BsAb drugs for solid tumors are now undergoing evaluation in clinical trials. In this review, we will introduce the formats of bispecific antibodies, and then update the latest preclinical studies and clinical trials in solid tumors of BsAbs targeting EpCAM, CEA, PMSA, ErbB family, and so on. Finally, we discuss the BsAb-related adverse effects and the alternative strategy for future study.

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“…Across various r/r solid malignant tumors, it showed a disease control rate of 66% (40/61) in an ongoing phase 1/2 trial (NCT03917381), while it has hepatitis, hypothyroidism, and fatigue as the main adverse events [ 96 ]. “Two-half” antibodies have also been developed using other platforms, for example, the biparatopic anti-HER2 antibody MBS301 by Mabworks currently in phase 1 (NCT03842085), the anti- BCMA/CD3 Elranatamab (PF-06863135) by Pfizer in phase 2 for r/r MM (NCT04649359), the anti-PD1/PD-L1 IBI318 by Innovent in several phase 1/2 trials for advanced tumors, alone or combined with lenvatinib or chemotherapy (see Supplementary Table S1 ), and the anti-PD1/PD-L1 LY3434172 based on Zymeworks’ Azymetric platform in phase I testing also for advanced cancers (NCT03936959) [ 97 ].…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

Elshiaty

Schindler

Christopoulos

2021

IJMS

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Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future.

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Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity

Cited by 43 publications

References 42 publications

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

Recent advances and challenges of bispecific antibodies in solid tumors

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

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