Critical examination of cohesive-zone models in the theory of dynamic fracture

We have examined a class of cohesive-zone models of dynamic mode-I fracture, looking both at steady-state crack propagation and its stability against out-of-plane perturbations. Our work is an extension of that of Ching, Langer, and Nakanishi (CLN) (Phys. Rev. E, vol. 53, no. 3, p. 2864 (1996)), who studied a non-dissipative version of this model and reported strong instability at all non-zero crack speeds. We have reformulated the CLN theory and have discovered, surprisingly, that their model is mathematically ill-posed. In an attempt to correct this difficulty and to construct models that might exhibit realistic behavior, we have extended the CLN analysis to include dissipative mechanisms within the cohesive zone. We have succeeded to some extent in finding mathematically well posed systems; and we even have found a class of models for which a transition from stability to instability may occur at a nonzero crack speed via a Hopf bifurcation at a finite wavelength of the applied perturbation. However, our general conclusion is that these cohesive-zone models are inherently unsatisfactory for use in dynamical studies. They are extremely difficult mathematically, and they seem to be highly sensitive to details that ought to be physically unimportant.Comment: 19 pages, REVTeX 3.1, epsf.sty, also available at http://itp.ucsb.edu/~lobkovs

Development and characterisation of monoclonal antibodies specific for the murine inhibitory Fc gamma RIIB (CD32B)

Tumourgenetics and immunogenetic

Immunotherapy targeting inhibitory Fc? receptor IIB (CD32b) in the mouse is limited by monoclonal antibody consumption and receptor internalization

Genetic deficiency of the inhibitory Fc receptor, Fc?RIIB (CD32b), has been shown to augment the activity of activatory Fc?R and promote mAb immunotherapy. To investigate whether mAbs capable of blocking Fc?RIIB have similar capacity, we recently generated a panel of specific anti-mouse Fc?RIIB mAbs that do not cross-react with other FcRs, allowing us to study the potential of Fc?RIIB as a therapeutic target. Previous work revealed a number of these mAbs capable of eliciting programmed cell death of targets, and in the present study we demonstrated their ability to promote target cell phagocytosis. However, in a variety of murine tumor models, anti-Fc?RIIB mAbs demonstrated limited therapeutic activity despite optimized treatment regimens. Unexpectedly, we observed that the anti-Fc?RIIB mAbs are rapidly and extensively consumed in vivo, both by the tumor and host cells, including B cells, leading to a precipitous loss from the circulation. Closer analysis revealed that the anti-Fc?RIIB mAbs become extensively internalized from the cell surface within 24 h in vivo, likely explaining their suboptimal efficacy. Subsequent studies revealed that anti-Fc?RIIB mAb immunotherapy was effective when used against Fc?RIIB+ tumors in Fc?RIIB?/? recipients, indicating that consumption of the mAb by nontumor cells is the primary limitation of these reagents. Importantly, similar rates of internalization were not seen on human target cells, at least in vitro. These studies further highlight the need to determine the propensity of mAb therapeutics to internalize target receptors and also identify potential key differences between human and mouse cells in this respect

Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity

Anti-CD40 monoclonal antibodies (mAbs) comprise agonists and antagonists, which display promising therapeutic activities in cancer and autoimmunity, respectively. We previously showed that epitope and isotype interact to deliver optimal agonistic anti-CD40 mAbs. The impact of Fc engineering on antagonists, however, remains largely unexplored. Here, we show that clinically relevant antagonists used for treating autoimmune conditions can be converted into potent FcyR-independent agonists with remarkable antitumor activity by isotype switching to hIgG2. One antagonist is converted to a super-agonist with greater potency than previously reported highly agonistic anti-CD40 mAbs. Such conversion is dependent on the unique disulfide bonding properties of the hIgG2 hinge. This investigation highlights the transformative capacity of the hIgG2 isotype for converting antagonists to agonists to treat cancer.Functional Genomics of Systemic Disorder

Isotype switching converts anti-CD40 antagonism to agonism to elicit potent antitumor activity

Anti-CD40 monoclonal antibodies (mAbs) comprise agonists and antagonists, which display promising therapeutic activities in cancer and autoimmunity, respectively. We previously showed that epitope and isotype interact to deliver optimal agonistic anti-CD40 mAbs. The impact of Fc engineering on antagonists, however, remains largely unexplored. Here, we show that clinically relevant antagonists used for treating autoimmune conditions can be converted into potent FcyR-independent agonists with remarkable antitumor activity by isotype switching to hIgG2. One antagonist is converted to a super-agonist with greater potency than previously reported highly agonistic anti-CD40 mAbs. Such conversion is dependent on the unique disulfide bonding properties of the hIgG2 hinge. This investigation highlights the transformative capacity of the hIgG2 isotype for converting antagonists to agonists to treat cancer