Selecting an Optimal Antibody for Antibody- Drug Conjugate Therapy

Abstract

Selection of appropriate targets is likely the most important consideration for the success of an antibody-drug conjugate (ADC) development program. Target selection for ADCs can be classified into two principal approaches: target-first and antibody-first approach or agnostic approach (Fig. 3.1). In the target-first approach, a target is chosen based on a set of factors, including expression pattern, abundance and internalization properties, and an antibody-generation campaign is focused on isolation of antibodies against this target. In the agnostic approach, antibodies capable of binding to and internalizing in tumor cells are isolated, followed by retrospective identification of their targets. While the target-first approach may have the advantage of a higher degree confidence in the suitability and novelty of the target based on prior knowledge of target properties, it requires significant work before internalizing antibodies become available. By contrast, the agnostic approach leads quickly to reagents suitable for testing hypotheses directly, although this strategy tends to favor highly expressed surface antigens, which are likely to have been described previously.

The Interplay of Antigen Affinity, Internalization, and Pharmacokinetics on CD44-Positive Tumor Targeting of Monoclonal Antibodies

“…Increasing mAb binding affinity and valence improves tumor uptake. − Moreover, high-affinity, bivalent binding mAbs can lead to greater in vitro potency than their lower avidity counterparts that recognize an identical epitope . However, critically, a high affinity mAb selected during standard screening and selection campaigns can exhibit poor tumor penetration, off-target tissue uptake, and rapid cell uptake and catabolism. − These observations are attributed to two phenomena. The first phenomenon is coined the binding-site barrier (BSB), which predicts the diffusion of a high affinity mAb into tumors is limited by the low local concentration of diffusible, free antibody due to slow rates of antibody–antigen dissociation. − The second phenomenon limiting mAb tumor uptake is coined target-mediated drug disposition (TMDD).…”

Antibody-Drug Conjugates: Functional Principles and Applications in Oncology and Beyond

“…The fundamental step of ADC development remains the selection of target-antigen [7,8]. The optimal target-antigen should be characterized by tumor-specific and homogeneous expression pattern, high levels of expression, rapid internalization, and minimal ectodomain shedding.…”