CD30 as a Therapeutic Target for Lymphoma

Abstract

Hodgkin's lymphoma (HL) and ALK(+) anaplastic large-cell lymphoma (ALCL) have become highly curable due to the success of modern regimens of chemotherapy and radiotherapy. However, up to one-third of the patients experience relapse or do not respond to first-line therapy, and half of them relapse again after secondary therapy with limited options for further treatment. In the last 15 years, monoclonal antibodies (mAbs) directed to surface receptors became a new and valuable therapeutic option in many hematologic malignancies. Due to its restricted expression on normal activated lymphocytes and its high expression on malignant cells, CD30 represents an attractive target molecule for HL and ALCL therapy. However, unconjugated CD30 mAbs have demonstrated a lack of objective clinical responses in patients with recurrent HL. CD30 exhibits complex signaling pathways, and binding of its natural ligand or anti-CD30 mAbs can induce apoptosis but may also promote proliferation and activation depending on the cellular context. Moreover, CD30 rapidly internalizes after crosslinking, which counteracts efficient recruitment of immunologic effectors but also provides the opportunity to transfer cytotoxic payloads coupled to CD30-specific mAbs into the tumor cells. Several tumor targeting approaches have been studied, including radio-immunoconjugates, immunotoxins, immunoRNases, immunokinases, and antibody drug conjugates (ADCs). In 2011, the ADC brentuximab-vedotin, consisting of the CD30-specific chimeric mAb cAC10 and the potent tubulin toxin monomethyl auristatin E, gained regulatory approval as a well tolerated and highly active drug in patients with refractory and relapsed HL and ALCL. SGN-35 is on the way to being incorporated in the standard management of CD30(+) lymphoma with significant therapeutic impact. This review gives a critical overview about anti-CD30 therapies with unconjugated, engineered, and conjugated mAbs and the therapeutic challenges of treatment of CD30(+) lymphoma.

CD30 expression in extranodal natural killer/T-cell lymphoma, nasal type among 622 cases of mature T-cell and natural killer-cell lymphoma at a single institution in South China

“…The recent availability of brentuximab vedotin, an anti-CD30 monoclonal antibody, has led to improved OS and FFS rates among patients with refractory Hodgkin lymphoma, which is characterized by strong and uniform expression of CD30 [6]. A similar benefit was observed for patients with ALCL, a T-cell lymphoma also characterized by the strong and uniform expression of CD30 in neoplastic cells [7]. We previously reported that CD30 is expressed in ENKTL [8]; however, the significance of CD30 expression in ENKTL remains unclear.…”

Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond

“…One of the earliest attempts was the development of an anti-CD30 monoclonal antibody called BerH2 and a single-chain variable fragment (scFv) linked to immunotoxins saporin-6 and pseudomonas exotoxin A, respectively [ 70 , 71 ]. A few other such therapies have since been trialled in various types of HL with some success [ 72 ], but the high reported toxicities make this unsuitable for ALCL. A similar approach that utilized an iodine-131 labelled murine anti-CD30 monoclonal antibody in HL achieved partial remissions [ 73 ], however toxicity was again found to be a barrier.…”

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

“…As mentioned above, an alternative target for the treatment of ALCL regardless of ALK status, is CD30, which is consistently present on ALCL cells, yet is restricted to activated T and B cells under homeostatic conditions, thereby limiting the risk of off‐target effects. Early attempts at developing antibody‐based drug delivery of toxins, such as saporin‐6 or pseudomonas exotoxin A, or radioisotopes, such as iodine‐131, to CD30‐positive cells proved too toxic for the paediatric setting (Pasqualucci et al , ; Klimka et al , ; Schnell et al , ; Schirrmann et al , ). The arrival of the anti‐CD30 antibody, SGN‐30, conjugated to BV (or SGN‐35), an anti‐microtubule agent monomethyl auristatin E, which targets CD30‐positive cells and delivers the antimitotic drug, has shown promise.…”