The new capabilities of the innovative AntibodyPlus Therapeutics go beyond ADCs

Cancer research

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Antibody (Ab) therapies are the most important drug class today. Developed to deliver cytotoxic payloads to tumors, these therapies are evolving to deliver new next-generation conjugates and treat various diseases beyond cancer.

“Among emerging antibody drugs, those in non-traditional formats, such as bispecific antibodies and antibody drug conjugates (ADCs), are becoming increasingly popular.” California-based biopharmaceutical consultant Yong Zhu, Ph.D., said 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 immunostimulating antibody conjugates and drug Ab+PROTAC (chimera-targeted proteolysis), Zhu wrote in a paper in Antibody therapy last October.

Bolt Biotherapeutics, Genentech and Innate Pharma are among the pioneers in this emerging field.

Bolt Biotherapeutics’ ISACs change the conversation

Bolt is developing immunostimulatory 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 and VP of immunology and pharmacology, said Biospace.

Michael Alonso_Bolt Biotherapies“Rather than using cytotoxics to kill the tumor, ISACs use immune stimulants to train the immune system to recognize and remember the tumor and its potential variants through a process called epitope diffusion and immunological memory.”

The mechanism of action begins with phagocytosis, in which phagocytes digest the tumor into peptide fragments. T cells see this in the context of immune stimulation, which drives T cell activation, epitope shedding and immunological memory, Alonso explained.

“The mechanism is quite convincing. ISACs have an active Fc component, so they may involve 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 main players.”

ISACs may be even more effective than checkpoint inhibitors, Alonso speculates. “The goal of checkpoint inhibitors is primarily to take the brakes off the T cells. CAR T therapy is great if the tumor expresses particular antigens, but otherwise 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 the antigen presentation of different neoantigens… which broadens the response repertoire. “This really jump-starts the system. The preclinical results are compelling.”

Bolt’s lead program is BDC-1001 for solid tumors that express HER 2, including those with low levels of HER-2. It combines a trastuzumab biosimilar with a proprietary TLR7/8 agonist to directly kill tumor cells, induce localized phagocytosis, activate myeloid APCs, and establish long-lasting immunity.

Alonso said Bolt aims to complete dose escalation and enrollment in a Phase I/II clinical trial this year and publish results in early 2023.

Another program, BDC-3042, is conceptually similar to ISACs, but with a different core molecule.

“It exploits a novel cell surface protein, Dectin-2, which is a C-type lectin receptor – essentially a phagocytic receptor expressed primarily by tumor-associated macrophages in the tumor microenvironment,” Alonso said.

“Bolt believes that the body treats cancer more like a wound that needs to heal rather than a pathogen that needs to be eliminated. You can change that if you agonize — or activate — tumor-associated phagocytes.” BDC-3042, an agonist antibody, has shown the potential to do so in preclinical studies.

While many new therapies fail to reach their hoped-for potential, Alonso admitted, “If we’re right about that, ISACs can actually transform the face of cancer therapies.”

This means eliciting lasting responses and safe and effective treatments. In the best-case scenario, he speculated, it might be possible to achieve widespread activation of the immune system against tumors, similar to how the immune system responds to and clears the flu.

The new Ab+ approach could offer a 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 degrader (BET) is delivered to the target, where it hijacks the ubiquitin-proteasome system to degrade specific proteins.

“I can’t talk about details until future research is published,” said Peter Dragovich, Ph.D., senior fellow, discovery chemistry at Genentech 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 therapies are not without their challenges, of course. For example, the potency of chimeric degradation molecules is sometimes lower than the legacy cytotoxic payloads that have been used for ADCs, Dragovich said. Therefore, “We often have to put more on the antibody,” to achieve the desired function, which makes the antibody 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. “Therefore, they often have very poor and very poor pharmacokinetic and drug metabolism properties live performance.”

Conjugating that chimeric degrading molecule to an antibody is one way to improve its function.

It is too early to discuss specific targets, as ‘chimeric degraders can target many different cell types,” Dragovich said. But broad-spectrum cytotoxic substitution offers the potential to broaden the distinction between cancer cells and normal cells and work in multiple therapeutic areas.

With these antibody conjugates, “What’s changing is the nature of the payload,” He continued. Ab+ approaches, such as DACs, “have the potential to provide a new class of payloads,” which differs from the broad spectrum cytotoxics provided in the past.

Ab+à la carte

Innate’s antibody+ approach includes ADCs, multispecific antibodies, and monoclonal antibodies. The company presented an update of its Phase II Tellomak study in cutaneous T-cell lymphoma (CTCL) involving its proprietary antibody, lacutamab, at the American Society of Hematology (ASH) Annual Meeting.

Yannis Morel_Innate PharmaThis program is based on “a tumor antigen-binding antibody that binds the molecule KIR3DL2,” Yannis Morel, Ph.D., Executive Board Member and EVP of Product Portfolio Strategy and Business Development, said Biospace in an interview.

Lacutamab, a simple monoclonal antibody, binds a chimeric antigen with an Fc and induces antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) via the Fc part of the antibody.

“It’s a rituximab-like antibody that depletes,” Morello said.

Lacutamab is in Phase II trials for Sézary syndrome, mycosis fungoides and peripheral T-cell lymphoma.

“We are showing very encouraging activity with a good safety profile,” Morel noted.

Also released at ASH were data on NK cell activation technology, called ANKET (Antibody-based NK cell Engager Therapeutics), developed by Innate and Sanofi.

“Here, we leveraged our antibody engineering capability to … (develop) multispecific antibodies.” Morello said. As a result, they can bind to molecules on cancer cells and activate NK cell receptors.

Innate has partnered with Sanofi on two ANKET programs. One, targeting CD123 in acute myeloid leukemia (AML), is in a Phase I/II trial. The other, targeting B-cell maturation antigen (BCMA) in multiple myeloma, is in preclinical development.

“Our newest innovation, IPH6501, incorporates a cytokine in NK cell activator, so we are targeting NK cells and inducing their proliferation.” Morello said. “One of the main challenges is to be able to produce this molecule in the first place, because it is very complex.”

That said, “Early indications suggest that our format is activating an activating receptor on NK cells called NKp46, which is very specific for NK cells.” Morello said. “There will only be activation if the engager binds to the tumor cells, so this is really an antigen-dependent activation of NK cells.”

This work updates the cancer immune cycle, he added, by placing NK cells in that cycle.

“T cells are not autonomous. They need help from the innate immune system to start the cycle, and that’s what NK cells are doing.”

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