Design and Preclinical Evaluation of a Novel B7-H4–Directed Antibody–Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305

Kinneer, Krista; Wortmann, Philipp; Cooper, Zachary A.; Dickinson, Niall J.; Masterson, Luke A.; Cailleau, Thais; Hutchinson, Ian; Vijayakrishnan, Balakumar; McFarlane, Mary; Ball, Kathryn; Davies, Michael; Lewis, Arthur; Huang, Yue; Rosenbaum, Anton I.; Yuan, Jijun; Chesebrough, Jon; Anderton, Judith; Novick, Steven; Wang, Jixin; Dimasi, Nazzareno; Christie, R. James; Sabol, Darrin; Tosto, Frances Anne; Wallez, Yann; Leo, Elisabetta; Albertella, Mark R.; Staniszewska, Anna D.; Tice, David A.; Howard, Philip W.; Luheshi, Nadia; Sapra, Puja

doi:10.1158/1078-0432.ccr-22-2630

Cited by 31 publications

(7 citation statements)

References 53 publications

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“…The three C-10 methyl analogs bearing a carbamate ( FD1 ), a urea ( FD2 ), or a sulfonamide ( FD3 ) at the C-7 position were linked through primary alcohols using a self-immolative aminomethylene spacer to obtain DL1–4 . For analogs FD4 , FD5 , FD6 , and FD7 the tetrapeptide cleavage sequence was directly attached to the C-10 amine via an enzymatically cleavable amide bond ( 23 ) to obtain DL9–14 . Compound FD5 , bearing both an alcohol group at C-7 and an amine at C-10 was linked two ways (direct peptide attachment at C-10 ( DL11 and DL12 ) or a self-immolative aminomethylene group at the C-7 alcohol ( DL5 and DL6 )) allowing for direct comparison between the two linking strategies.…”

Section: Resultsmentioning

confidence: 99%

Design and Evaluation of ZD06519, a Novel Camptothecin Payload for Antibody Drug Conjugates

Petersen,

Brant,

Lasalle

et al. 2024

Molecular Cancer Therapeutics

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In recent years, the field of antibody drug conjugates (ADCs) has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs incorporating camptothecin-based topoisomerase I inhibitor payloads. Herein, we present the development of a novel camptothecin ZD06519 (FD1), which has been specifically designed for its application as an ADC payload. A panel of camptothecin analogs with different substituents at the C-7 and C-10 positions of the camptothecin core were prepared and tested in vitro. Selected compounds spanning a range of potency and hydrophilicity were elaborated into drug-linkers, conjugated to trastuzumab, and evaluated in vitro and in vivo. ZD06519 was selected based on its favourable properties as a free molecule and as an antibody conjugate, which include moderate free payload potency (~1 nM), low hydrophobicity, strong bystander activity, robust plasma stability, and high-monomeric ADC content. When conjugated to different antibodies using a clinically validated MC-GGFG-based linker, ZD06519 demonstrated impressive efficacy in multiple CDX models and noteworthy tolerability in healthy mice, rats, and non-human primates.

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Section: Resultsmentioning

confidence: 99%

Design and Evaluation of ZD06519, a Novel Camptothecin Payload for Antibody Drug Conjugates

Petersen,

Brant,

Lasalle

et al. 2024

Molecular Cancer Therapeutics

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“…On the basis of the difference in tumor progression, or lack thereof, in the human cohorts and mouse models, future understanding of the mechanisms of B7-H4 in vivo are essential to rule out or include B7-H4 as a potential biomarker for future patients with breast cancer. Instead of an immune checkpoint, B7-H4 could be a better target for antibody–drug conjugate (ADC) development, as multiple companies are doing ( 64, 66 ). In fact, to our knowledge, there are no B7-H4 blocking antibodies in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer

Wescott,

Sun,

Gonzalez-Ericsson

et al. 2024

Cancer Research Communications

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Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1–sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. Significance: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.

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“… 9 Other B7-H4-directed ADCs in clinical development use different drug-linker payload systems including a topoisomerase I inhibitor payload (DAR=8) and a site-specifically conjugated microtubule-disrupting auristatin payload (DAR=6). 45 46 SGN-B7H4V is distinct from other B7-H4-directed ADCs in that it leverages the clinically validated vedotin drug-linker payload technology platform.…”

Section: Discussion/conclusionmentioning

confidence: 99%

SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models

Gray,

Ulrich,

Epp

et al. 2023

J Immunother Cancer

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BackgroundSGN-B7H4V is a novel investigational vedotin antibody–drug conjugate (ADC) comprising a B7-H4-directed human monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine citrulline (mc-vc) linker. This vedotin linker-payload system has been clinically validated in multiple Food and Drug Administration approved agents including brentuximab vedotin, enfortumab vedotin, and tisotumab vedotin. B7-H4 is an immune checkpoint ligand with elevated expression on a variety of solid tumors, including breast, ovarian, and endometrial tumors, and limited normal tissue expression. SGN-B7H4V is designed to induce direct cytotoxicity against target cells by binding to B7-H4 on the surface of target cells and releasing the cytotoxic payload MMAE upon internalization of the B7-H4/ADC complex.MethodsB7-H4 expression was characterized by immunohistochemistry across multiple solid tumor types. The ability of SGN-B7H4V to kill B7-H4-expressing tumor cells in vitro and in vivo in a variety of xenograft tumor models was also evaluated. Finally, the antitumor activity of SGN-B7H4V as monotherapy and in combination with an anti-programmed cell death-1 (PD-1) agent was evaluated using an immunocompetent murine B7-H4-expressing Renca tumor model.ResultsImmunohistochemistry confirmed B7-H4 expression across multiple solid tumors, with the highest prevalence in breast, endometrial, and ovarian tumors. In vitro, SGN-B7H4V killed B7-H4-expressing tumor cells by MMAE-mediated direct cytotoxicity and antibody-mediated effector functions including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. In vivo, SGN-B7H4V demonstrated strong antitumor activity in multiple xenograft models of breast and ovarian cancer, including xenograft tumors with heterogeneous B7-H4 expression, consistent with the ability of vedotin ADCs to elicit a bystander effect. In an immunocompetent murine B7-H4-expressing tumor model, SGN-B7H4V drove robust antitumor activity as a monotherapy that was enhanced when combined with an anti-PD-1 agent.ConclusionThe immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates robust antitumor activity in preclinical models through multiple potential mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies.

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Design and Preclinical Evaluation of a Novel B7-H4–Directed Antibody–Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305

Cited by 31 publications

References 53 publications

Design and Evaluation of ZD06519, a Novel Camptothecin Payload for Antibody Drug Conjugates

Design and Evaluation of ZD06519, a Novel Camptothecin Payload for Antibody Drug Conjugates

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer

SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models

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