Product information and disease description Product description Product information Pharmacology

Pharmacodynamics

8 evidence topics · 8 sources

B7-H4 expression and prognosis in ACC subtypes

“ACC-I tumors overexpressed the immune checkpoint B7-H4, and the degree of immune exclusion was directly correlated with B7-H4 expression levels, an independent predictor of poor survival.” (opens the source at this quote in a new tab)
“B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target.” (opens the source at this quote in a new tab)

“ACC-I, the most aggressive type of ACC, is characterized by solid histology, NOTCH1 mutation enrichment, early development of metastasis including to visceral organs and poor prognosis (median overall survival (mOS) = 3.4 ys).” (opens the source at this quote in a new tab)
“Notably, our RNA-seq analysis, revealed significant upregulation of B7-H4, an inhibitory immune checkpoint, particularly in ACC-I” (opens the source at this quote in a new tab)
“No other immune checkpoint proteins were expressed at significant levels in ACC.” (opens the source at this quote in a new tab)

B7-H4 expression by histologic subtype: 265-case immunohistochemistry cohort

“We performed immunohistochemical analysis of five ADC targets (EGFR, TROP2, B7-H4, Nectin-4, and AXL) across 265 ACC cases (193 non-solid subtype and 72 solid subtype) and examined their expression in relation to clinicopathological features, histological subtypes, and prognosis.” (opens the source at this quote in a new tab)
“Conversely, B7-H4 and Nectin-4 showed moderate-to-high expression in 59% and 55% of the overall cohort, but were notably enriched in the aggressive solid subtype, with high expression observed in 66% and 75% of cases, respectively.” (opens the source at this quote in a new tab)
“High B7-H4 and Nectin-4 expression levels were independently associated with reduced overall survival (p < 0.05), whereas EGFR and TROP2 expression showed no significant prognostic value.” (opens the source at this quote in a new tab)

“Notably, in adenoid cystic carcinoma, or ACC, 94% of tumors exhibit some level of expression and high B7-H4 expression is correlated with worse prognosis.” (opens the source at this quote in a new tab)

Preclinical activity of XMT-1660 and relationship to B7-H4 expression

“In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression.” (opens the source at this quote in a new tab)
“As expected, based on the targeted delivery mediated by an ADC, the activity of XMT-1660 correlated with target expression (Fig. 5B; Supplementary Fig. S9), which suggests that in the clinic, it may be possible to prospectively enrich for responders based on the expression of B7-H4.” (opens the source at this quote in a new tab)

Preclinical B7-H4-directed ADC activity in ACC patient-derived xenografts (class evidence, AZD8205)

“Two ACC-I/B7-H4-high PDXs obtained 90% complete responses to a single dose of AZD8205, but none were observed with isotype-conjugated payload or in an ACC-II/B7-H4 low PDX.” (opens the source at this quote in a new tab)

Clinical relationship between dose, B7-H4 expression, and activity: all tumor types

“Clinical activity was correlated with both dose and B7-H4 expression.” (opens the source at this quote in a new tab)

Clinical relationship between B7-H4 expression and activity: participants with ACC

“The median B7-H4 tumor proportion score (TPS) was 77.5% (range, 2%-100%) among 40 evaluated patients, and 66.7% harbored activating NOTCH1-4 mutations.” (opens the source at this quote in a new tab)
“B7-H4 expression level did not clearly predict benefit.” (opens the source at this quote in a new tab)
“Some patients with expression as low as 2% have evidence of durable and deep responses” (opens the source at this quote in a new tab)

B7-H4 expression in tumor and normal tissue in the AZD8205 development program (class evidence, AZD8205)

“To address this gap, we developed a validated IHC protocol (Supplementary Fig. S2) and used it to assess the expression of B7-H4 across a large panel of normal tissues and 2145 tumor samples across 15 indications.” (opens the source at this quote in a new tab)
“In contrast, B7-H4 was detected in a limited number of normal human tissues, such as fallopian tube, lung, breast, and prostate, and was generally found in <10% of the total cells in the sample, restricted toward ductal or tubular epithelium, and primarily located on the apical luminal membrane (Supplementary Table S3).” (opens the source at this quote in a new tab)

Bystander killing and patient-derived xenograft activity of a B7-H4-directed topoisomerase I inhibitor ADC (class evidence, AZD8205)

“AZD8205 was cytotoxic to the target-negative HT29-GFP cells only when in co-culture with the target-positive HT29-huB7-H4 cells (Fig. 3A), clearly demonstrating a bystander-killing effect.” (opens the source at this quote in a new tab)
“The antitumor activity of AZD8205 was evaluated in a panel of 26 TNBC PDX models that represent a range of B7-H4 staining intensity and heterogeneity (Fig. 4A) as was observed in the TNBC patient samples (Figs. 1C and 4B).” (opens the source at this quote in a new tab)
“Upon a single intravenous administration of 3.5 mg/kg AZD8205, the best response according to modified RECIST criteria was complete or partial response in 18 (69%), stable disease in 2 (8%), and progressive disease in 6 (23%; Fig. 4C).” (opens the source at this quote in a new tab)
“Seven of the seven RAD51-negative PDX models (100%) responded to 3.5 mg/kg AZD8205 treatment, and five of seven (71%) achieved complete response (Fig. 5A).” (opens the source at this quote in a new tab)
“These results indicate that the level of target expression needed for ADC activity is context dependent and that incorporation of warhead sensitivity biomarkers could further refine approaches for patient selection.” (opens the source at this quote in a new tab)