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Re: AMGN bought FPRX for 80% Premium - MA Heating up?"ADAM9 is overexpressed in multiple solid tumors relative to its expression in normal tissues which have a 'low level' of expression whatever that is. It is apparently ubiquitous in many human cell types as you have pointed out. Not only is the marker differentially expressed between tumors and normal tissues but the ADC is efficiently internalized and degraded by the tumors. In addition, preclinical studies have shown excellent cytotoxicity in tumor cell lines and mouse models. 936 showed favorable safety studies in monkeys with no new toxicities reported other that those known with the DMX profile even after repeated dosing." Not to be picky for nit-picking's sake, but this basically held for every other compound they've ever tried in the clinic, such as the failed IMGN289, and the less than spectacular IMGN901, IMGN779, Coltuximab Ravtansine etc. There is another subtlety to animal models transplanted with patient derived xenografts: animal versions of the receptor don't always cross react with the human versions that are expressed on the grafts and so these models allow for much higher doses without toxicity and the results seem better as well. Note for example: In humans physiological expression of Mesothelin is found in epithelial layers of the pleura, the peritoneum and the pericard, in salivary glands, in the bone marrow, the cornea and in intestinal tissues [28]. Utilizing Mesothelin as a tumor target is therefore afflicted with unwanted cross-reactivity. Keratitis, neuropathy, fatigue, anorexia, asthenia, diarrhea and LFT increase are the most common drug-related laboratory abnormalities which restrict the maximum tolerated dose in clinical trials to 6.5 mg/kg (q3w) [29]. In mouse models MSLN-ADC can be administered in significantly higher doses since Anetumab ravtansine does not crossreact with murine Mesothelin. Considering the different pharmacokinetics between humans and mice a dose of 6.5 mg/kg q3w (MTD in humans) corresponds to 15 mg/kg q2w in mice [14]. There aren't detailed reports yet about ADAM9 models, although a couple of points work in its favor: 1) the Immunogen poster indicates the base antibody is cynomolgus cross reactive and 2) the drug to antibody ratio is a uniform and low 2:1. Still, there's no guarantee expression is uniform between humans and monkeys and that toxicity can be avoided in humans. Again, there are good reasons to be optimistic about IMGC936, and Macrogenics thinks it's likely that they will enter dose escalation, but it's early yet. |
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Msg # | Subject | Author | Recs | Date Posted |
51915 | Re: AMGN bought FPRX for 80% Premium - MA Heating up? | MRHIROLLER | 2 | 3/7/2021 3:32:56 PM |