ADCT-602, a Novel PBD Dimer-containing Antibody-Drug Conjugate for Treating CD22-positive Hematologic Malignancies.

Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody-drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 is a novel CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer-based payload tesirine. In preclinical studies, ADCT-602 demonstrated potent, specific cytotoxicity in CD22-positive lymphomas and leukemias. ADCT-602 was specifically bound, internalized, and trafficked to lysosomes in CD22-positive tumor cells; after cytotoxin release, DNA interstrand crosslink formation persisted for 48 hours. In the presence of CD22-positive tumor cells, ADCT-602 caused bystander killing of CD22-negative tumor cells. A single ADCT-602 dose led to potent, dose-dependent, in vivo antitumor activity in subcutaneous and disseminated human lymphoma/leukemia models. Pharmacokinetic analyses (rat and cynomolgus monkey) showed excellent stability and tolerability of ADCT-602. Cynomolgus monkey B cells were efficiently depleted from circulation after one dose. Gene signature association analysis revealed IRAK1 as a potential marker for ADCT-602 resistance. Combining ADCT-602 + pacritinib was beneficial in ADCT-602-resistant cells. Chidamide increased CD22 expression on B-cell tumor surfaces, increasing ADCT-602 activity. These data support clinical testing of ADCT-602 in R/R B-ALL (NCT03698552) and CD22-positive hematologic cancers.

Comparison of Pyrrolobenzodiazepine Dimer Bis-imine versus Mono-imine: DNA Interstrand Cross-linking, Cytotoxicity, Antibody-Drug Conjugate Efficacy and Toxicity.

Antibody-drug conjugates (ADC) delivering pyrrolobenzodiazepine (PBD) DNA cross-linkers are currently being evaluated in clinical trials, with encouraging results in Hodgkin and non-Hodgkin lymphomas. The first example of an ADC delivering a PBD DNA cross-linker (loncastuximab tesirine) has been recently approved by the FDA for the treatment of relapsed and refractory diffuse large B-cell lymphoma. There has also been considerable interest in mono-alkylating PBD analogs. We conducted a head-to-head comparison of a conventional PBD bis-imine and a novel PBD mono-imine. Key Mitsunobu chemistry allowed clean and convenient access to the mono-imine class. Extensive DNA-binding studies revealed that the mono-imine mediated a type of DNA interaction that is described as "pseudo cross-linking," as well as alkylation. The PBD mono-imine ADC demonstrated robust antitumor activity in mice bearing human tumor xenografts at doses 3-fold higher than those that were efficacious for the PBD bis-imine ADC. A single-dose toxicology study in rats demonstrated that the MTD of the PBD mono-alkylator ADC was approximately 3-fold higher than that of the ADC bearing a bis-imine payload, suggesting a comparable therapeutic index for this molecule. However, although both ADCs caused myelosuppression, renal toxicity was observed only for the bis-imine, indicating possible differences in toxicologic profiles that could influence tolerability and therapeutic index. These data show that mono-amine PBDs have physicochemical and pharmacotoxicologic properties distinct from their cross-linking analogs and support their potential utility as a novel class of ADC payload.

Efficacy, Tolerability, and Pharmacokinetic Studies of Antibody-Drug Conjugates Containing a Low-Potency Pyrrolobenzodiazepine Dimer.

Antibody-drug conjugate (ADC) research has typically focused on the release of highly potent cytotoxic agents to achieve antitumor efficacy. However, recently approved ADCs trastuzumab deruxtecan and sacituzumab govitecan release lower-potency topoisomerase inhibitors. This has prompted interest in ADCs that release lower-potency cytotoxic drugs to potentially enhance therapeutic index and reduce unwanted toxicity. Pyrrolobenzodiazepine (PBD) dimer ADCs have been widely investigated in human clinical trials, which have focused on high-potency PBDs. In this study, we evaluated five ADCs that release the low-potency PBD dimer SG3650. The relatively low clogD for this agent facilitated higher drug-to-antibody ratio (DAR) conjugation without the need for antibody engineering or functionalization of the drug. The rank order of potency for DAR 2 site-specific ADCs (conjugated at the C239i position) matched the order for the corresponding free drugs in vitro. Despite free drug SG3650 being inactive in vivo, the DAR 2 ADCs derived from the corresponding drug-linker SG3584 showed antitumor efficacy in solid (anti-HER2) and hematologic (anti-CD22) xenograft models. Antitumor activity could be enhanced by conjugating SG3584 to trastuzumab at higher DARs of 4 and 8 and by adjusting dosing and schedule. Higher-DAR conjugates were stable and displayed good rat pharmacokinetic profiles as measured by ELISA and LC/MS-MS. A single intravenous dose of isotype control SG3584 DAR 2 ADC resulted in no mortality in rats or monkeys at doses of up to 25 and 30 mg/kg, respectively. These findings suggest that further investigations of low-potency PBD dimers in ADCs that target hematologic and solid tumors are warranted.

Intervenção fisioterapêutica no paciente queimado: uma abordagem pneumofuncional em estudo piloto / Physiotherapeutic intervention in burned patient: a respiratory therapy approach in a pilot study / Intervención fisioterapéutica en paciente quemado: una aproximación pneumofuncional en un estudio piloto

Introdução: As queimaduras representam um grave problema médico-social no Brasil e no mundo, atingindo principalmente crianças abaixo de 5 anos e idosos, sendo responsáveis por cerca de 240 mil mortes no mundo. Objetivo: Analisar os benefícios da fisioterapia respiratória no paciente queimado, comparar os marcadores funcionais antes e depois da intervenção fisioterapêutica e correlacionar volume inspiratório com pressão inspiratória máxima nos pacientes da Unidade de Tratamento de Queimados (UTQ) de Sergipe. Método: A amostra foi composta por seis pacientes internados na UTQ. Trata-se de um estudo piloto, de intervenção, de aspecto comparativo, sendo utilizada uma amostra por conveniência na UTQ. Para a avaliação pneumofuncional, foram utilizados o Voldyne, a cirtometria, a manuvacuometria e o peak flow. Resultados: Dos pacientes atendidos, 50% foram do gênero masculino, com média de idade de 32,5 anos, sendo que 50% das queimaduras foram causadas por álcool em combustão. A região corporal mais atingida foi o tórax e todos da amostra apresentaram queimadura nessa região. Conclusões: Após as sessões de fisioterapia, foi possível observar uma resposta pneumofuncional satisfatória nos pacientes queimados, por meio dos marcadores funcionais. É de grande importância que, a partir deste estudo piloto, sejam realizadas novas pesquisas seguindo essa metodologia.

Introduction: Burns represent a serious medical and social problem in Brazil and worldwide, affecting mainly the elderly and children below the age of five, which represents approximately 240 thousand deaths in the world. Objective: The purpose of this study was to analyze the benefits of the respiratory therapy for burn injuries; compare the functional markers before and after the rehabilitation; recognize the principal respiratory complications in the patient with burns; and correlate the inspiratory volume with the maximal respiratory pressure of the patients from the Burn Unit Care in Sergipe. Method: The sample was composed of six patients admitted to the Burn Unit Care. This is a pilot study of rehabilitation with comparative aspects, and with the use of a sample for convenience at Burn Unit Care. Voldyne, cirtometry, peak flow, and manometer were used for the respiratory therapy evaluation. Results: Fifty percent (50 percent) of the sample were consisted of men, on the average age of 32.5 years-old; alcohol in combustion caused 50% of the burns; and the most affected part of the body was the chest and all patients from the sample presented burns there. Conclusions: It was possible to notice an increase in the pulmonary volume of the sample patients after the physical therapy sessions. It is of great importance to carry out new studies after this pilot study by using this method.

Introducción: Quemaduras representan un problema médico y social en Brasil y en todo el mundo, que afecta principalmente a los niños menores de cinco años y las personas mayores, lo que representa alrededor de 240.000 muertes en todo el mundo. Objetivo: El objetivo de este estudio fue analizar los beneficios de la terapia respiratoria en pacientes con quemaduras, comparar los marcadores funcionales antes y después de la intervención de terapia física y correlacionar el volumen inspiratorio con la presión inspiratoria máxima en pacientes Unidad de Tratamiento Quemado Sergipe. Método: La muestra consistió en seis pacientes hospitalizados en la unidad de cuidado de quemaduras. Se trata de un estudio piloto, la intervención, aspecto comparativo, se utiliza una muestra de conveniencia en la Unidad de Tratamiento de Quemaduras. Para la evaluación del pecho, se utilizó el Voldyne, cirtometry el flujo manuvacuometria y pico. Resultados: De los pacientes tratados, el 50% eran mujeres y 50% hombres, con una edad media de 32,5 años, y el 50% de las quemaduras fueron causadas por la combustión del alcohol. La región del cuerpo más afectado fue el pecho y toda la muestra se había quema en esta región. Conclusión: Después de las sesiones de terapia física, se observó una respuesta satisfactoria en pacientes con quemaduras, observamos a través de los marcadores funcionales. Es muy importante que, a partir de este estudio piloto se llevó a cabo estudios complementarios tras esta metodología.

Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine fused chlorins as very active photodynamic agents for melanoma cells.

The development of new stable 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins with high absorption properties at 650 nm, and their impressive photosensitizer ability against melanotic and amelanotic cancer cells is described. Comparison between a diester-substituted chlorin with the corresponding dihydroxymethyl derivative demonstrated that the increased hydrophilicity of the latter is crucial to ensure nanomolar activity against melanoma cells. The new photosensitizer leads to death of human melanoma cells being both apoptosis and necrosis in equal parts involved in the treatment response. The dihydroxymethyl-chlorin was particularly active against human melanocytic melanoma A375 cells, which can be viewed as a solution to overcome the resistance of melanotic melanoma to photodynamic therapy.

Targeting triple-negative breast cancer cells with 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles.

Further studies on 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as anticancer agents against breast cancer are reported, allowing to demonstrate the potential of these compounds for the therapy of the triple-negative breast cancer, the most challenging tumors in clinical practice. These compounds were assayed for their in vitro cytotoxicity on several human breast cancer cell lines (MCF7, HCC1954 and HCC1806 cell lines). Particularly interesting were the results obtained for 4-hydroxyphenyl substituted derivative, which proved to be the most promising compound regarding HCC1806 cell line, a triple-negative breast cancer. The effects of the two most active compounds on cell survival, viability, cell cycle, DNA damage and expression of proteins related to cell death pathways were studied. The reported results consolidate the potential of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles for the therapy of breast cancer, particularly the triple-negative.

Local strategies to address health needs of individuals with orofacial clefts in alagoas, Brazil.

Objective : To describe demographic and clinical-genetic characteristics of patients from a poor area of Brazil and to share experience on how the local genetic unit has addressed their major health needs. Design : Descriptive cohort. Setting : A clinical-genetic unit, a cytogenetics unit, and a regional cleft team located in the northeast and southeast of Brazil. Participants : A total of 133 individuals with orofacial clefts who attended the surgical call of a nongovernmental organization. From this group, 125, 77, and 13 patients completed phases 1, 2, and 3, respectively. Methods : Phase 1 comprised a description of demographic characteristics recorded through interviews. Phase 2 included a clinical-genetic evaluation using a pretested form, as well as cytogenetic analyses of selected patients. Phase 3 comprised collaborative action to address major health needs of patients without primary surgery. The Fisher test was used for statistics with p value < .05. Results : A majority of patients were rural residents with isolated cleft lip with cleft palate. Ages ranged between 0 and 30 years. Fifty percent had never undergone surgery; whereas, 100% had never attended a genetic evaluation. Isolated cleft was diagnosed in 77.9%, syndromes in 14.3%, and multiple congenital abnormalities in 7.8%. Positive familial history of clefts occurred in 28%; whereas, parental consanguinity was present in 7.8% cases. A total of 23 individuals without cleft surgery were registered for multidisciplinary treatment. Conclusions : Findings revealed high levels of unmet medical needs and provided an evidence base for health care planning. Collaborative action was crucial and might be applied to other regions in Brazil.