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Mmae Efficacy

FIGURE 3 The repeat epitope-binding 3A5 ADC is more efficacious than the single epitope-binding 11D10 ADC. (A) Scatchard analysis of anti-MUC16 binding to OVCAR-3 cells. (B) Inhibition of in vitro cell proliferation by auristatin conjugates of human Fc chimeric 3A5 and 11D10. Conjugates were applied continuously to OVCAR-3 cells for five days. Concentrations are 9 mg/mL, and serial threefold dilutions are down to 1.4 ng/mL. Viable cell numbers were measured using an ATP-dependent luminescent assay and are expressed as counts per second. Data from untreated cells are plotted at 0.45 ng/mL. 3A5-MC-MMAF (filled diamonds and dashed lines), 3A5-VC-MMAE (filled squares and solid lines), 11D10-MC-MMAF (open diamonds and dashed lines), and 11D10-VC-MMAE (open squares and solid lines). (C) In vivo efficacy of armed anti-MUC16 antibodies (Ab-VC-MMAE conjugates) against OVCAR-3/luc mouse xenografts.

FIGURE 3 The repeat epitope-binding 3A5 ADC is more efficacious than the single epitope-binding 11D10 ADC. (A) Scatchard analysis of anti-MUC16 binding to OVCAR-3 cells. (B) Inhibition of in vitro cell proliferation by auristatin conjugates of human Fc chimeric 3A5 and 11D10. Conjugates were applied continuously to OVCAR-3 cells for five days. Concentrations are 9 mg/mL, and serial threefold dilutions are down to 1.4 ng/mL. Viable cell numbers were measured using an ATP-dependent luminescent assay and are expressed as counts per second. Data from untreated cells are plotted at 0.45 ng/mL. 3A5-MC-MMAF (filled diamonds and dashed lines), 3A5-VC-MMAE (filled squares and solid lines), 11D10-MC-MMAF (open diamonds and dashed lines), and 11D10-VC-MMAE (open squares and solid lines). (C) In vivo efficacy of armed anti-MUC16 antibodies (Ab-VC-MMAE conjugates) against OVCAR-3/luc mouse xenografts.

Antibody Therapeutics 41

example, CD30 ADCs bearing increasing copies of drug (2, 4, and 8 drugs per Ab) showed a corresponding trend toward lower IC50s. However, the benefit was not observed in a xenograft model, wherein their in vivo antitumor activities were largely comparable. In fact, the therapeutic index actually increased with decreased DAR because of the better tolerability (144). In addition, ADCs with a higher DAR were shown to exhibit more rapid clearance compared with one with a lower drug load, minimizing the exposure at tumor sites (144). One must recognize, however, that the rapid metabolism of an ADC with higher DAR may lead to higher levels of active metabolites in systemic circulation and, consequently, greater toxicity. Given the potency of these cytotoxic agents, once a minimal efficacious threshold is reached, any further increase in drug load may offer very little, if any, benefit. Another possibility is that overmodification of an Ab with lipophilic drugs shifts the tissue distribution toward increased nonspecific uptake (e.g., liver, spleen) and increases normal organ toxicity. The nature of the target must also be considered, including the level of expression, the degree of internalization upon binding, and drug sensitivity.

Optimizing in vitro characteristics in the absence of in vivo context such as PK and metabolism may not yield the benefit one would expect. Another example is the impact of linker stability on efficacy. ADC linker technology has evolved into a vast array of varieties, including labile linkers, such as hydrazone and disulfide linkers, and peptidic linkers that are stable in serum but can be readily degraded in intracellular compartments by specific enzymes including lysosomal proteases (136,145). The mechanism of action for ADCs requires cleavage of the linker; this might possibly occur through enzymatic cleavage or chemical degradation of the linker in plasma, or through catabolism of the Ab within the lysosome or other intracellular organelles (146). In theory, more stable linkers allow for maximal intratumoral drug delivery and more efficient drug release at the target site. However, this must be evaluated in the context of many other factors. In a recent study on peptidic amide linkers for CD70 ADC, a more stable bromoacetamidecaproyl (bac) linker was compared with mal-eimidocaproyl (mc) linker. The bac linkers showed increased plasma stability and a higher intratumoral drug exposure relative to the mc linker, yet they shared similar in vivo activity profiles (147). In this case, further extension of linker half-life rendered limited benefit. Once again, it highlights the importance of identifying rate-limiting steps in translating from in vitro to in vivo.

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