Developed initially to deliver cytotoxic payloads to tumors, antibody therapeutics are evolving to provide new, next-generation conjugates and treat various diseases beyond cancer.
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Antibody (Ab) therapeutics are the most prominent class of drugs today. Developed to deliver cytotoxic payloads to tumors, these therapies are evolving to provide new, next-generation conjugates and treat various diseases beyond cancer.
“Among the emerging antibody drugs, those in the non-traditional formats are becoming more and more popular, such as bispecific antibodies and antibody-drug conjugates (ADCs),” California-based biopharma consultant Yong Zhu, Ph.D., told BioSpace in an interview. This is based on their ability to achieve better efficacy with less severe side effects than cytotoxic payloads.
Some of the most exciting include immune-stimulating antibody conjugates and Ab+ PROTAC (proteolysis targeting chimera) drugs, Zhu wrote in a paper in Antibody Therapeutics last October.
Bolt Biotherapeutics, Genentech and Innate Pharma are among the pioneers in this emerging field.
Bolt Biotherapeutics’ ISACs are Conversation Changers
Bolt is developing immune-stimulating antibody conjugates (ISACs) that are “similar to antibody-drug conjugates in construction, but are very different in their biology,” Michael Alonso, Ph.D., scientific co-founder & VP of immunology & pharmacology, told BioSpace.
“Rather than using cytotoxics to kill the tumor, ISACs utilize immune stimulants to train the immune system to recognize and remember the tumor and its potential variants through a process called epitope spreading and immunological memory.”
The mechanism of action starts with phagocytosis, in which phagocytes digest the tumor into peptide fragments. T cells see that in the context of immune stimulation, which drives T cell activation, epitope spreading and immunological memory, Alonso explained.
“The mechanism is quite compelling. ISACs have an active Fc component, so they can engage the natural killer (NK) cells. We know that when NK cells interact with phagocytes in the context of immune stimulants, their activity can be enhanced, but phagocytes and T cells are the major players.”
ISACs maybe even more effective than checkpoint inhibitors, Alonso speculates. “Checkpoint inhibitors’ goal is primarily to take the brakes off the T cells. CAR T therapy is fantastic if the tumor expresses particular antigens, but if not, the therapy is less effective. Our goal with ISACs is to take off the brakes and apply the gas.”
The “gas” in that analogy is antigen presentation of diverse neoantigens… which broadens the response repertoire. “That really jumpstarts the system. Preclinical results are compelling.”
Bolt’s lead program is BDC-1001 for HER 2-expressing solid tumors, including those with low levels of HER-2. It conjugates a trastuzumab biosimilar to a proprietary TLR7/8 agonist to kill tumor cells directly, induce localized phagocytosis, activate myeloid APCs and establish durable immunity.
Alonso said Bolt aims to complete dose escalation and enrollment in a Phase I/II clinical trial this year and release results early in 2023.
Another program, BDC-3042, is conceptually similar to ISACs, but with a different core molecule.
“It takes advantage of a novel cell surface protein, Dectin-2, which is a C-type lectin receptor - essentially a phagocytic receptor that is expressed primarily by tumor-associated macrophages in the tumor microenvironment,” Alonso said.
“Bolt believes the body treats the tumor more like a wound that needs to be healed rather than a pathogen to be eliminated. You can change that if you agonize – or activate – tumor-associated phagocytes.” BDC-3042, an agonistic antibody, has shown the potential to do this in preclinical studies.
While many new therapeutics fail to achieve their hoped-for potential, Alonso admitted, “If we are right on this, ISACs can actually transform the face of cancer therapeutics.”
That means eliciting durable responses and safe, effective treatments. In the very best scenario, he speculated, it may be possible to get widespread immune system activation against tumors, similar to how the immune system responds to and eliminates influenza.
Novel Ab+ Approach could Deliver New Class of Payloads
Genentech, a member of the Roche Group, is conjugating PROTAC molecules to antibodies in a degrader-antibody conjugate (DAC) approach to target protein degradation in cells expressing specific antigens.
Basically, a chimeric bromodomain and extra terminal (BET) degrader is delivered to the target, where it hijacks the ubiquitin-proteasome system to degrade specific proteins.
“I can’t talk about specifics until future research is published, Peter Dragovich, Ph.D., senior fellow, discovery chemistry at Genentech, told BioSpace in an interview. However, this approach “has the potential to be more targeted to a certain type of biology than the legacy cytotoxic payloads that have been used previously for other antibody-drug conjugates (ADCs).”
If this potential is realized, it may be possible to increase the therapeutic index for the resulting conjugate, he added.
DAC therapeutics aren’t without their challenges, of course. For example, the potency of the chimeric degrader molecules is sometimes less than the legacy cytotoxic payloads that have been used for ADCs, Dragovich said. Therefore, “We often must put more of them onto the antibody,” to achieve desired function, which makes the antibody look less natural.
“If you look at them through the lens of the chimeric degrader world, those molecules are lipophilic and tend to be very large – usually twice the size of a typical small molecule,” he continued. “Thus, they often have very poor pharmacokinetic and drug metabolism properties and very poor in vivo performance.”
Conjugating that chimeric degrader molecule to an antibody is one way to improve its function.
It’s too early to discuss specific targets, as “chimeric degraders can target many different cell types,” Dragovich said. But, replacing broad-spectrum cytotoxics offers the possibility of widening the distinction between cancer cells and normal cells and working in multiple therapeutic areas.
With these antibody conjugates, “What is changing is the nature of the payload,” he continued. Ab+ approaches, such as DACs, “have the potential to deliver a new class of payloads,” that differs from the broad spectrum cytotoxics delivered in the past.
Ab+ à la Carte
Innate’s antibody+ approach includes ADCs, multispecific antibodies and monoclonal antibodies. The company presented an update of the Phase II Tellomak study in cutaneous T-cell lymphoma (CTCL) involving its proprietary antibody, lacutamab, at the American Society of Hematology (ASH) annual meeting.
This program is based on “an antibody that binds to a tumor-associated antigen, the molecule KIR3DL2,” Yannis Morel, Ph.D., executive board member and EVP, product portfolio strategy and business development, told BioSpace in an interview.
Lacutamab is a monoclonal antibody that induces antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) through the Fc part of the antibody.
“It’s a depleting antibody like rituximab,” Morel said.
Lacutamab is in Phase II trials for Sézary syndrome and mycosis fungoides.
“We are showing very encouraging activity with a good safety profile,” Morel noted.
Data regarding Innate’s NK cell engager technology, Antibody-based NK cell Engager Therapeutics (ANKET), was also released at ASH.
“Here, we have leveraged our antibody engineering capability to develop multi-specific antibodies,” Morel said. Consequently, they can bind to molecules on the tumor cells and also activate receptors.
Innate has partnered with Sanofi on two ANKET programs. One, targeting CD123 in acute myeloid leukemia (AML), is in Phase I/II trials. The other, targeting B-cell maturation antigen (BCMA) in multiple myeloma, is in preclinical development.
“Our newest ANKET innovation, IPH6501, incorporates a cytokine in the NK cell engager so we are engaging the NK cells plus inducing their proliferation,” Morel said. “One of the main challenges is, first, to be able to produce this molecule, because it is complex.”
That said, “Early indications suggest our format is triggering an activating receptor on NK cells called NKp46, which is very specific for NK cells,” Morel said. “There will be an activation solely if the engager is binding to the tumor cells, so this is really antigen-dependent activation of the NK cells.”
This work updates the cancer immunity cycle, he added, by putting NK cells into that cycle.
“T cells are not autonomous. They need help from the innate immune system to start the cycle, and that’s what the NK cells are doing.”
