Barriers to antibody therapy in solid tumors, and their solutions

Abstract

Antibody drugs have become the mainstream of cancer treatment due to advances in cancer biology and Ab engineering. However, several barriers to Ab therapy have also been identified. These include various mechanisms for Ab drug resistance, such as heterogeneity of antigen expression in tumor cells and reduction in antitumor immunity due to expression diversity, polymorphism of Fc receptors (FcR) in effector cells, and reduced function of effector cells. Countermeasures to each resistance mechanism are being investigated. This review focuses on barriers that impede the delivery of Ab drugs due to features of the solid tumor microenvironment. Unlike hematological malignancies, in which the target tumor cells are in blood vessels, clinical solid tumors contain cancer stroma, which interferes with the delivery of Ab drugs. In addition, the cancer mass itself interferes with the penetration of Ab drugs. In this article, I will consider the etiology of cancer stroma and propose a new Ab drug development strategy for solid cancer treatment centering on cancer stromal targeting (CAST) therapy using anti-insoluble fibrin Ab-drug conjugate (ADC), which can overcome the cancer stroma barrier. The recent success of ADCs, chimeric antigen receptor T cells (CAR-Ts), and Bi-specific Abs is changing the category of Ab drugs from molecular-targeted drugs based on growth signal inhibition to cancer-specific targeted therapies. Therefore, at the end of this review, I argue that it is time to reorient the concept of Ab drug development.

Keywords: ADC; CAST therapy; EPR effect; antibody; antibody drug resistance; blood coagulation; cancer specificity; cancer stroma; insoluble fibrin.

FIGURE 1

Diagram of the enhanced permeability retention (EPR) effect. (A) Small molecules easily leak from normal vessels, but macromolecules (including IgG) are too large to pass through normal vessel walls. (B) Even macromolecules can extravasate from tumor vessels and be retained in the tumor tissue for long periods of time due to the EPR effect (modified from Matsumura [2012]26)

FIGURE 2

Structural change from fibrinogen to fibrin clot, and discovery of a unique pit in the fibrin clot. The epitope in the pits is a hydrophobic region on the β chain; in the soluble state, this region interacts closely with its counterpart region on the γ chain (modified from Hisada et al [2013]25). FDP, fibrin degradation product

FIGURE 3

Kinetics of fibrin deposition in several nonmalignant disease models and PET/computed tomography (CT) with anti‐insoluble fibrin (IF) mAb probe in spontaneous tumor models. Anti‐IF mAb cross‐reacted with mouse (Ms) or rat fibrin (Fib) clots. Immunohistochemistry (IHC) indicated that fibrin clot formation occurred only in the acute phase of nonmalignant diseases, and these clots virtually disappeared within a few weeks and were substituted by collagen in the late phase. Radiolabeled anti‐IF mAb (PET probe) was injected into mice bearing chemically induced cutaneous tumors with abundant IF‐rich stroma. The PET/CT scans show clear and specific accumulation in tumors (modified from Hisada et al [2013]²⁵). AG, autoradiography ; BSA, bovine serum albumin ; Fng, fibrinogen; Hu, human

FIGURE 4

Diagram of cancer stromal targeting therapy (anti‐insoluble fibrin (IF)‐drug conjugate). The Ab‐drug conjugate (ADC) selectively accumulates in tumor tissues due to the enhanced permeability retention (EPR) effect, binds to the specific pits in the fibrin clot, and creates a scaffold from which effective sustained release of free anticancer agent (ACA) occurs. Free ACA is only released when the ADC is bound to epitopes in insoluble fibrin because plasmin is active only on IF and is neutralized by endogenous α2‐plasmin inhibitor circulating in the blood. The free ACA can easily reach the tumor (modified from Fuchigami et al [2018]28)

FIGURE 5

Binding site barrier. An Ab‐drug conjugate (ADC) with higher affinity does not always exert higher antitumor activity. Penetration efficiency should be more seriously considered in clinical practice. Immunofluorescence staining revealed that 1084ADC was distributed evenly in all BxPC3 tumors, confirming the efficient penetration of 1084ADC into the central region of the tumors. In contrast, 1849ADC was mainly localized near blood vessels (modified from Tsumura et al [2018]34). K_a, association rate constant; K_d, dissociation rate constant; K_D, dissociation constant; SPR, surface plasmon resonance; TF, tissue factor

FIGURE 6

Various modes of action of Ab therapeutics. Typical modes of action (MOA) for Ab therapy were selected. The Abs shown in blue boxes act primarily by inhibiting cancer growth signals. Cancer specificity is of the utmost importance for the Ab drugs shown in red boxes. ADC, Ab‐drug conjugate; CAR‐T, chimeric antigen receptor T cell