Abstract P4-14-28: XMT-1522 induces tumor regressions in pre-clinical models representing HER2-positive and HER2 low-expressing breast cancer

Abstract XMT-1522 is an anti-HER2 antibody-drug conjugate (ADC) comprised of a novel anti-HER2 antibody (HT-19) and the Dolaflexin ADC platform, which allows for conjugation of 12-15 proprietary auristatin drug payload molecules per antibody without aggregation or detrimental impact on pharmacokinetics. The HT-19 antibody binds to a novel HER2 extracellular domain epitope and does not compete for HER2 binding with trastuzumab or pertuzumab. In vitro, XMT-1522 has sub-nanomolar potency in cell lines expressing as few as 25,000 HER2 antigens per cell, and is ∼100X more potent than ado-trastuzumab emtansine (T-DM1) across a panel of 25 cell lines representing a range of tumor indications and HER2 expression levels. In the BT-474 HER2-positive breast cancer model, treatment with the HT-19 antibody alone at a single 5 mg/kg dose is inactive, while XMT-1522 ADC at a single 2 mg/kg or 5 mg/kg dose induces durable complete tumor regression, indicating that the primary mechanism of XMT-1522 is cytotoxic payload delivery, not inhibition of HER2 signaling. T-DM1 at a single 5 mg/kg dose in the same model is inactive, consistent with the significant improvement in potency of XMT-1522 compared to T-DM1. Biodistribution studies using a HER2-targeted Dolaflexin ADC in the BT-474 model demonstrate accumulation of intact ADC and released active drug payload in tumor at levels significantly higher than normal tissues. In a HER2-positive patient-derived xenograft (PDX) model, XMT-1522 induces durable complete tumor regression after a single 1 mg/kg dose, while T-DM1 at a 10 mg/kg dose achieves tumor growth delay without regression. In a HER2 1+ PDX model without HER2 gene amplification, a single 3 mg/kg dose of XMT-1522 achieves partial tumor regression where a 10 mg/kg dose of T-DM1 is inactive. Combination of XMT-1522 with trastuzumab does not block the ability of the ADC to bind HER2 or efficiently internalize, and in vivo the combination of low dose XMT-1522 with full dose trastuzumab and pertuzumab is synergistic in a HER2-driven model. The exposure achieved with XMT-1522 at well-tolerated doses in cynomolgus monkey is several fold higher than the exposure needed in mice to achieve complete tumor regressions across models representing a range of HER2 expression and tumor indications. Based on these data, XMT-1522 will soon enter clinical testing in breast cancer patients with both HER2-positive tumors and HER2 low-expressing (IHC 1+ and 2+/FISH-) tumors. Citation Format: Bergstrom DA, Bodyak N, Park PU, Yurkovetskiy A, DeVit M, Yin M, Poling L, Thomas JD, Gumerov D, Xiao D, Ter-Ovanesyan E, Qin L, Uttard A, Johnson A, Lowinger TB. XMT-1522 induces tumor regressions in pre-clinical models representing HER2-positive and HER2 low-expressing breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-28.</jats:p

Edaphic constraints on seed germination and emergence of three Acacia species for dryland restoration in Saudi Arabia

In situ edaphic factors affecting seed germination and seedling emergence of three framework species of Acacia were investigated with the intent of developing fundamental and scalable restoration capacity for Arabian dryland restoration. Direct seeding represents the most efficient means to restore vegetation at the landscape scale and this study provides insight into edaphic and ecological limitations, as well as effective protocols governing the use of native seeds for restoration in hyper-arid environments. The study was conducted in extant Acacia woodland habitat on conserved land (Thumamah Nature Park) in close proximity to Riyadh, Saudi Arabia. Broad-scale direct seeding using un- and pretreated Acacia gerrardii, A. tortilis, and A. ehrenbergiana seed, and two seed burial depths were implemented across three sites with distinct soil surface characteristics. Eight weeks post-sowing, random samples for each species × seed treatment × burial depth combination were excavated, sieved, and categorized as follows: failed to germinate, germinated but died prior to emerging, or successfully emerged. We show that germination and emergence of Acacia gerrardii, A. tortilis, and A. ehrenbergiana were driven by a three-way interaction among species, site, and seed burial depth. Treating seed with the signaling compound Moddus did not have a definitive effect, positive or negative, on any of the species investigated. Acacia gerrardii was the only species that exhibited widespread emergence, though emergence was not consistent across sites or burial depths. Germination was highest in disturbed soil (up to 69% for A. gerrardii), but very few (&lt;2%) successfully emerged; a greater proportion of germinants in sandy soil emerged (up to 44% for A. gerrardii) even though the overall germination was less. Though species-dependent, a 2-cm sowing depth was most effective in sand; while in disturbed soil, sowing depths of 1 and 2 cm were comparable; and no germination was observed in gravelly clay soil. Sandy soil exhibited rapid water infiltration (107.6 mm min-1), and post-sowing surface crusting was a non-factor (0.44 kg cm-2). Disturbed soil exhibited moderate water infiltration (1.46 mm min-1) and post-sowing surface crusting was double that of sand (0.88 kg cm-2) and restrictive on seedling emergence. Gravelly clay exhibited extremely poor water infiltration (0.12 mm min-1), and surface crusting was severe (4.49 kg cm-2) and an order of magnitude greater than sand. The medium-coarse sand fraction, a key driver of the observed soil surface processes, was greatest in sand (55%) and significantly less and uniform in the disturbed (22%) and gravelly clay (22%) soils. Our findings demonstrate that soil surface characteristics and associated processes can dictate ecological processes at depths as shallow as 1–2 cm, and that soil crusts that slow water infiltration and impede seedling emergence rapidly reconstitute after disturbance; both are important considerations for restoring dryland vegetation