SynopsisOver the past couple of decades, antibody-drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics.
Two 120-d trials (May to September, 1988 and 1989) determined the effects of grazing tall fescue (two varieties) or orchardgrass on forage intake and performance by beef cows. Each summer, 48 cow-calf pairs grazed endophyte-infected Kentucky-31 tall fescue (KY-31), endophyte-free Mozark tall fescue (MOZARK), or Hallmark orchardgrass (OG) pastures (16 pairs/treatment). Forage OM intakes and digestibilities were determined during June and August each year. Cow and calf BW and milk production were determined every 28 d. During June of both years, OM intakes did not differ (P greater than .10) among treatments. During August of 1988, intakes were 18% lower (P less than .05) by KY-31 cows (1.6% of BW) than by MOZARK or OG cows (average 1.95% of BW); however, no differences (P greater than .10) were measured in August of 1989. Estimates of ergovaline consumption during June from KY-31 were between 4.2 (1988) and 6.0 mg/d (1989), whereas August estimates were between 1.1 (1988) and 2.8 mg/d (1989). Ergovaline in MOZARK estrusa was below detection limits, except in August of 1989. Cows that grazed KY-31 lost three times (P less than .01) more BW than cows that grazed MOZARK or OG (42 vs 9 and 13 kg, respectively). Milk production by KY-31 cows was 25% lower (P less than .01) than that by cows that grazed MOZARK or OG (6.0 vs average of 8.0 kg/d). Similarly, slower (P less than .01) calf gains were noted for KY-31 than for MOZARK or OG (.72 vs .89 and .88 kg/d, respectively). Cows grazing KY-31 experienced accelerated BW loss and reduced milk production and weaned lighter calves than did cows grazing MOZARK or OG. Decreased performance was not explained by consistently reduced forage intakes; hence, altered nutrient utilization was suspected.
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