Assorted Skin Procedures: Foreign Body Removal, Cryotherapy, Electrosurgery, and Treatment of Keloids.

Clinicians in the primary care setting will encounter various different skin conditions requiring procedural intervention. There are many different procedural approaches to treatment. Knowing which modalities are available and best suited to handle a particular skin lesion allows for flexibility for patient and clinician. Although some treatment modalities may be used more than others, it is helpful to be at least familiar with basic in office skin procedures such as removal of foreign bodies, cryotherapy, electrosurgery, and treatment of keloids, as these procedures are helpful in addressing the wide variety of the most commonly encountered skin issues in primary care.

A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers.

c-Met is a well-characterized oncogene that is associated with poor prognosis in many solid tumor types. While responses to c-Met inhibitors have been observed in clinical trials, activity appears to be limited to those with MET gene amplifications or mutations. We developed a c-Met targeted antibody-drug conjugate (ADC) with preclinical activity in the absence of MET gene amplification or mutation, and activity even in the context of moderate protein expression. The ADC utilized a high-affinity c-Met antibody (P3D12), that induced c-Met degradation with minimal activation of c-Met signaling, or mitogenic effect. P3D12 was conjugated to the tubulin inhibitor toxin MMAF via a cleavable linker (vc-MMAF). P3D12-vc-MMAF demonstrated potent in vitro activity in c-Met protein-expressing cell lines regardless of MET gene amplification or mutation status, and retained activity in cell lines with medium-low c-Met protein expression. In contrast, the c-Met tyrosine kinase inhibitor (TKI) PHA-665752 slowed tumor cell growth in vitro only in the context of MET gene amplification or very high protein expression. This differential activity was even more marked in vivo. P3D12-vc-MMAF demonstrated robust inhibition of tumor growth in the MET gene amplified MKN-45 xenograft model, and similar results in H1975, which expresses moderate levels of wild type c-Met without genomic amplification. By comparison, the c-Met TKI, PHA-665752, demonstrated modest tumor growth inhibition in MKN-45, and no inhibition at all in H1975. Taken together, these data suggest that P3D12-vc-MMAF may have a superior clinical profile in treating c-Met positive malignancies in contrast to c-Met pathway inhibitors.

TR1801-ADC: a highly potent cMet antibody-drug conjugate with high activity in patient-derived xenograft models of solid tumors.

cMet is a well-characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody-drug conjugates (ADCs). However, the clinical benefit from cMet-targeted therapy has been limited. We developed a novel cMet-targeted 'third-generation' ADC, TR1801-ADC, that was optimized at different levels including specificity, stability, toxin-linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site-specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin-linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet-expressing cell lines but also in medium-to-low cMet cell lines (40 000-90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low-medium cMet expression were also very responsive to TR1801-ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801-ADC had excellent efficacy with significant antitumor activity in 90% of tested patient-derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single-dose administration. Altogether, TR1801-ADC is a new generation cMet ADC with best-in-class preclinical efficacy and good tolerability in rats.

A bispecific antibody that targets IL-6 receptor and IL-17A for the potential therapy of patients with autoimmune and inflammatory diseases.

Despite the success of current biological therapeutics for rheumatoid arthritis, these therapies, targeting individual cytokines or pathways, produce beneficial responses in only about half of patients. Therefore, better therapeutics are needed. IL-6 and IL-17A are proinflammatory cytokines in many autoimmune and inflammatory diseases, and several therapeutics have been developed to specifically inhibit them. However, targeting both of these cytokines with a bispecific therapeutic agent could account for their nonoverlapping proinflammatory functions and for the fact that IL-6 and IL-17A act in a positive feedback loop. Here, we present the development of MT-6194, a bispecific antibody targeting both IL-6R and IL-17A that was developed with the FynomAb technology. We also present data from mouse inflammatory disease experiments, indicating that simultaneous inhibition of both IL-6 and IL-17A yields enhanced efficacy compared with inhibition of each cytokine alone.

BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties.

Rituximab (chimeric anti-CD20 mAb) is currently used in the treatment of B-NHL and B cell malignancies, alone or in combination with chemotherapy. However, subsets of patients do not initially respond and/or develop resistance to additional treatments. Hence, there is a need to develop more effective anti-CD20 mAbs that may improve clinical response. BM-ca is a novel humanized anti-CD20 mAb that was tested against several B-NHL cell lines and was compared to several anti-CD20 mAbs (Rituximab, ofatumumab, 2H7, B1 and B-Ly1). BM-ca was shown to strongly induce both homotypic cell aggregation and redistribution of CD20 to membrane lipid rafts. BM-ca was also able to induce programmed cell death (apoptosis) without the need for cross-linking and demonstrated potent complement-dependent cytotoxicity (CDC). BM-ca was more cytotoxic than rituximab even in malignant B cells expressing low amounts of membrane CD20. Type I anti-CD20 mAbs typically induce minimal levels of homotypic cell aggregation and apoptosis but strong localization of CD20 to lipid rafts and potent CDC. Type II anti-CD20 mAbs typically exert the reverse activities. Noteworthy, BM-ca exhibits properties that are shared by both type I and type II anti-CD20 mAbs, which may reflect the recognition of a new CD20 epitope and/or exhibit different molecular signaling. Overall, the present data show that BM-ca is a novel anti-CD20 mAb that may be classified as a type I/II. The therapeutics efficacy of BM-ca awaits its use in clinical trials.

Novel humanized anti-CD20 monoclonal antibodies with unique germline VH and VL gene recruitment and potent effector functions.

The anti-CD20 chimeric monoclonal antibody (mAb) rituximab is the most widely used therapeutic antibody for B-cell malignancies. However, approximately 50% of non-Hodgkin's lymphoma (B-NHL) patients respond to treatment with this antibody. Novel humanized antibodies target membrane CD20 with enhanced effector properties should improve treatment for a broader patient population with relapsed and refractory disease. A novel chimerized form of the murine anti-CD20 1K1791 exerts more potent antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities and induces cell death by a non-caspase dependent process. Humanized mAbs derived from 1K1791 were designed using four different humanization techniques and characterized. In contrast to rituximab or 2F2 (human anti-CD20 mAb), several of these exhibited superior ADCC, CDC, inhibition of cell growth and cell death. There was a wide range of functional differences among the humanized forms of 1K1791 despite a modest replacement of amino acid residues in the CDRs. To determine whether the superior activities exhibited by parental murine mAb 1K1791 were due to differences in VH and VL rearrangement, we analyzed its germline and compared it to other anti-CD20 mAbs. A remarkable conservation of VH and Vk (VL kappa) gene usage was observed in the murine anti-CD20 mAbs. 18/23 used the same germline gene J558.42 and 4/23 used closely related genes of the 'J558' group. Thus, 22/23 belonged to VH1 family. One exception was the mAb 1K1791, which was derived from the VH9.12 germline gene. 1K1791 was also unique in its use of a Vk19/28 family gene whereas most other mAbs (21/23) used Vk4/5 family genes. A formal relationship between the particular germline gene recruitment and antibody functionality has not been established, however, the present findings identified humanized mAbs with functional activities that were superior to rituximab and 2F2. These in vitro results support future in vivo animal testing and subsequent clinical trials.

CD154 regulates primate humoral immunity to influenza.

Current methods of immunosuppression for the purposes of allowing solid organ transplantation in humans are broadly inhibitory and thus are associated with an increased risk of opportunistic infections and neoplasia. We have shown previously that a selective blockade of CD40-CD154 interactions during heart transplantation in cynomolgus macaques significantly delays immune-mediated graft injury. Here, we determined the effect of anti-CD154 mAb therapy on primate serologic responses to immunization with influenza virus hemagglutinin (HA), a T-cell-dependent Ag. We found that CD154 blockade attenuated primary and secondary serum Ab responses of IgM and IgG isotypes to influenza, even when anti-CD154 treatment was discontinued prior to reimmunization. These findings show that in primates CD40-CD154 interactions are necessary for both primary and secondary Ab responses to viral Ags. Furthermore, the data suggest that viral Ag stimulation of primates in the absence of CD154 stimulation may have a tolerizing effect on that Ag.